Pkm2 modulators and methods for their use

ABSTRACT

Compounds having activity as PKM2 activators are disclosed. The compounds have the following structure (I): including stereoisomers, tautomers, pharmaceutically acceptable salts and prodrugs thereof, wherein R1, R2, R3, R4, R5 and R6 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is generally directed to novel PKM2 modulators anduse of the same for treatment of various cancers.

2. Description of the Related Art

Proliferation of cancer cells requires the accumulation of sufficientbiosynthetic building blocks (i.e., biomass) to replicate each nucleicacid, protein and lipid in the cell. As a tumor grows, the need fornutrients and oxygen can exceed the capacity of poorly vascularizedblood vessels. Faced with such challenges, cancer cells must be able toadjust metabolic pathways.

Glucose provides cancer cells with building blocks in the form ofglycolytic pathway intermediates (Mazurek S., Int. J. Biochem. Cell.Biol. 43(7):969-80 (2010); Vander Heiden M. G., Cantley L. C., ThompsonC. B., Science 324(5930):1029-33 (2009)). The main enzyme regulatingflux through the glycolitic pathway in cancer cells, and thus the levelof available intermediates, is the M2 splice form of pyruvate kinase(PKM2), which controls the rate-limiting final step in glycolysis. PKM2is allosterically regulated by fructose-1,6-bisphosphate (FBP), anupstream glycolytic intermediate that binds to and converts PKM2 from aless active dimeric form with low affinity for its substrate,phosphoenolpyruvate (PEP), to an active tetrameric form with high PEPaffinity (Ashizawa K., Willingham M. C., Liang C. M., Cheng S. Y., J.Biol. Chem. 266(25):16842-46 (1991); Mazurek S., Boschek C. B., Hugo F.,Eigenbrodt E., Semin. Cancer Biol. 15(4):300-08 (2005)). When glucose isabundant, FBP levels increase and PKM2 is activated, leading to highglycolytic flux. When glucose is limiting, FBP levels decrease and PKM2is inactivated, allowing upstream glycolytic intermediates to accumulateand be diverted into biosynthetic pathways (Mazurek S., Michel A.,Eigenbrodt E., J. Biol. Chem. 272(8):4941-52 (1997)).

PKM2 is upregulated in cancer cells (Altenberg B., Greulich K. O.,Genomics 84(6):1014-20 (2004)), and has been shown to increasetumorigenicity compared to the alternatively spliced and constitutivelyactive PKM1 isoform (Christofk H. R., Vander Heiden M. G., Harris M. H.,et al., Nature 452(7184):230-33 (2008); Goldberg M. S., Sharp P. A., J.Exp. Med. 209(2):217-24 (2012)). Specific RNAi knockdown of PKM2 hasalso been shown to regress established xenograft tumors (Goldberg M. S.,Sharp P. A., J. Exp. Med. 209(2):217-24 (2012)). These findings indicatethat control of glycolytic flux through PKM2 activation/inactivation isimportant for tumor growth.

PKM2 has recently been shown to have a critical function in regulatingserine biosynthesis. Serine is synthesized de novo from glycolyticintermediate 3-phosphoglycerate, and serine itself is used in thesynthesis of nucleotides, proteins, lipids, and glutathione (Locasale J.W., Cantley L. C., Cell Cycle 10(22):3812-13 (2011)). When serine isabsent from the growth media, PKM2 expressing cells reduce glycolyticflux (presumably through PKM2 inactivation) and accumulate glycolyticintermediates such as 3-phosphoglycerate. This allows PKM2 expressingcells to proliferate in serine-depleted media to a significantly greaterdegree than cells expressing PKM1 (Ye J., Mancuso A., Tong X., et al.Proc. Nat'l Acad. Sci. U.S.A. 109(18):6904-09 (2012)). Serine, like FBP,is an allosteric activator of PKM2 (Eigenbrodt E., Leib S., Kramer W.,Friis R. R., Schoner W., Biomed. Biochem. Acta. 42(11-12):5278-82(1983)). It is thus likely that when cellular serine levels aresufficiently high, PKM2 is converted to the active tetrameric form,restoring glycolytic flux to lactate.

Cancer cells inactivate PKM2 through multiple mechanisms, includingoncoprotein binding (Kosugi M., Ahmad R., Alam M., Uchida Y., Kufe D.,PLoS One 6(11):e28234 (2011); Zwerschke W., Mazurek S., Massimi P.,Banks L., Eigenbrodt E., Jansen-Durr P., Proc. Nat'l Acad. Sci. U.S.A.96(4):1291-96 (1999)), tyrosine phosphorylation (Hitosugi T., Kang S.,Vander Heiden M. G., et al., Sci. Signal 2(97):ra73 (2009); Presek P.,Glossmann H., Eigenbrodt E., et al., Cancer Res. 40(5):1733-41 (1980);Presek P., Reinacher M., Eigenbrodt E., FEBS Lett. 242(1):194-98(1988)), lysine acetylation (Lv L., Li D., Zhao D., et al., Mol. Cell42(6):719-30 (2011)), cysteine oxidation (Anastasiou D., PoulogiannisG., Asara J. M., et al., Science 334(6060):1278-83 (2011)), and prolylhydroxylation (Chen N., Rinner O., Czernik D., et al., Cell Res.21(6):983-86 (2011)). In each case, decreased PKM2 activity correlateswith increased tumorigenicity. It was recently shown that PKM2 mutationsthat inhibit tetramerization also increase tumorigenicity (Gao X., WangH., Yang J. J., Liu X., Liu Z. R., Mol. Cell 45(5):598-609 (2012)). Inlight of such evidence, efforts have focused on the discovery anddevelopment of small molecule PKM2 activators (Boxer M. B., Jiang J. K.,Vander Heiden M. G., et al., J. Med. Chem. 53(3):1048-55 (2010); JiangJ. K., Boxer M. B., Vander Heiden M. G., et al., Bioorg. Med. Chem.Lett. 20(11):3387-93 (2010); Walsh M. J., Brimacombe K. R., Veith H., etal., Bioorg. Med. Chem. Lett. 21(21):6322-27 (2011)) as a potentiallyuseful anti-cancer therapy for treatment of sarcoma, brain, colorectal,kidney, head and neck, lung, ovarian, pancreatic and prostate cancers.PKM2 activators can also be used in combination of chemotherapeuticagent(s) to treat the above conditions.

While progress has been made in this field, there remains a need in theart for improved PKM2 modulators (e.g., activators), which are usefulfor treatment of any number of cancers. The present invention fulfillsthis need and provides further related advantages.

BRIEF SUMMARY OF THE INVENTION

In brief, the present invention is directed to compounds having activityas PKM2 modulators, including stereoisomers, tautomers pharmaceuticallyacceptable salts and prodrugs thereof, and the use of such compounds fortreatment of various cancers. In certain embodiments, the compounds areactivators of PKM2.

In one embodiment, compounds having the following structure (I) areprovided:

or a stereoisomer, pharmaceutically acceptable salt, tautomer or prodrugthereof, wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as defined herein.

In another embodiment, a pharmaceutical composition is providedcomprising a compound having structure (I), or a stereoisomer,pharmaceutically acceptable salt, tautomer or prodrug thereof, and apharmaceutically acceptable carrier, diluent or excipient.

In another embodiment, a method for modulating PKM2 in a mammal in needthereof is provided, the method comprising administering to the mammalan effective amount of a compound having structure (I), or astereoisomer, pharmaceutically acceptable salt, tautomer or prodrugthereof. In some embodiments, modulation of PKM2 comprises activatingPKM2. In some embodiments the method is for treatment of cancer.

These and other aspects of the invention will be apparent upon referenceto the following detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

In the figures, identical reference numbers identify similar elements.The sizes and relative positions of elements in the figures are notnecessarily drawn to scale and some of these elements are arbitrarilyenlarged and positioned to improve figure legibility. Further, theparticular shapes of the elements as drawn are not intended to conveyany information regarding the actual shape of the particular elements,and have been solely selected for ease of recognition in the figures.

FIG. 1A depicts representative compounds.

FIG. 1B is a graph showing PKM2 activity of representative compounds.

FIG. 1C presents normalized PKM2 dose response curves for PEP.

FIG. 1D is a graph of normalized PKM2 dose response curves for ADP.

FIG. 2 illustrates a co-crystal structure of PKM2 in complex with arepresentative compound.

FIG. 3A provides pyruvate kinase activity in cells treated with arepresentative compound.

FIG. 3B is a gel showing tetramer formation induced by representativecompounds.

FIG. 3C shows pyruvate kinase activity data in cells as a function oftime after the representative PKM2 activator has been removed bywashing.

FIG. 4A demonstrates viability of lung adenocarcinoma cells treated withrepresentative compounds in the absence of serine.

FIG. 4B is a bar graph depicting rescue of PKM2 activator viability.

FIG. 4C depicts viability of a representative compound against a subsetof lung carcinoma cell lines in the absence of serine.

FIGS. 5A and 5B present tumor volume data in mice treated withrepresentative compounds.

FIGS. 6A and 6B illustrate PKM2 activation profiles for representativecompounds in A549 and NCI-H1299 lung cancer cells.

FIG. 7 presents nuclear exclusion assay results for representativecompounds.

FIG. 8 is a graph showing percent viability of A549 cells in the absenceof serine and in the presence of exemplary compounds.

FIG. 9 shows body weight data for mice treated with exemplary compounds.

DETAILED DESCRIPTION OF THE INVENTION

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments of theinvention. However, one skilled in the art will understand that theinvention may be practiced without these details.

Unless the context requires otherwise, throughout the presentspecification and claims, the word “comprise” and variations thereof,such as, “comprises” and “comprising” are to be construed in an open,inclusive sense, that is as “including, but not limited to”.

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least oneembodiment of the present invention. Thus, the appearances of thephrases “in one embodiment” or “in an embodiment” in various placesthroughout this specification are not necessarily all referring to thesame embodiment. Furthermore, the particular features, structures, orcharacteristics may be combined in any suitable manner in one or moreembodiments.

As used herein, the following terms have the following meanings:

“Amino” refers to the —NH₂ radical.

“Cyano” or “nitrile” refers to the —CN radical.

“Hydroxy” or “hydroxyl” refers to the —OH radical.

“Imino” refers to the ═NH substituent.

“Nitro” refers to the —NO₂ radical.

“Oxo” refers to the ═O substituent.

“Thioxo” refers to the ═S substituent.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, which is saturated orunsaturated (i.e., contains one or more double and/or triple bonds),having from one to twelve carbon atoms (C₁-C₁₂ alkyl), preferably one toeight carbon atoms (C₁-C₈ alkyl) or one to six carbon atoms (C₁-C₆alkyl), and which is attached to the rest of the molecule by a singlebond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl),n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl,2-methylhexyl, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl,penta-1,4-dienyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and thelike. Unless stated otherwise specifically in the specification, analkyl group may be optionally substituted.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, which is saturated orunsaturated (i.e., contains one or more double and/or triple bonds), andhaving from one to twelve carbon atoms, e.g., methylene, ethylene,propylene, n-butylene, ethenylene, propenylene, n-butenylene,propynylene, n-butynylene, and the like. The alkylene chain is attachedto the rest of the molecule through a single or double bond and to theradical group through a single or double bond. The points of attachmentof the alkylene chain to the rest of the molecule and to the radicalgroup can be through one carbon or any two carbons within the chain.Unless stated otherwise specifically in the specification, an alkylenechain may be optionally substituted.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl radical as defined above containing one to twelve carbon atoms.Unless stated otherwise specifically in the specification, an alkoxygroup may be optionally substituted.

“Alkoxyalkyl” refers to a radical of the formula —R_(b)OR_(a) whereR_(a) is an alkyl radical as defined above containing one to twelvecarbon atoms and R_(b) is an alkylene radical as defined above. Unlessstated otherwise specifically in the specification, an alkoxyalkyl groupmay be optionally substituted.

“Alkylamino” refers to a radical of the formula —NHR_(a) or —NR_(a)R_(a)where each R_(a) is, independently, an alkyl radical as defined abovecontaining one to twelve carbon atoms. Unless stated otherwisespecifically in the specification, an alkylamino group may be optionallysubstituted.

“Alkylaminoalkyl” refers to a radical of the formula —R_(b)NHR_(a) or—NR_(a)R_(a) where each R_(a) is, independently, an alkyl radical asdefined above containing one to twelve carbon atoms and R_(b) is analkylene radical as defined above. Unless stated otherwise specificallyin the specification, an alkylaminoalky group may be optionallysubstituted.

“Alkylsulfone” refers to a radical of the formula —S(O)₂R_(a) whereR_(a) is an alkyl radical as defined above containing one to twelvecarbon atoms and R_(b) is an alkylene radical as defined above. Unlessstated otherwise specifically in the specification, an alkylsulfonegroup may be optionally substituted.

“Hydroxylalkyl” refers an alkyl radical as defined above containing oneto twelve carbon atoms which has been substituted by one or morehydroxyl groups. Unless stated otherwise specifically in thespecification, hydroxylalkyl group may be optionally substituted.

“Thioalkyl” refers to a radical of the formula —SR_(a) where R_(a) is analkyl radical as defined above containing one to twelve carbon atoms.Unless stated otherwise specifically in the specification, a thioalkylgroup may be optionally substituted.

“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen,6 to 18 carbon atoms and at least one aromatic ring. For purposes ofthis invention, the aryl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which may include fused or bridgedring systems. Aryl radicals include, but are not limited to, arylradicals derived from aceanthrylene, acenaphthylene, acephenanthrylene,anthracene, azulene, benzene, chrysene, fluoranthene, fluorene,as-indacene, s-indacene, indane, indene, naphthalene, phenalene,phenanthrene, pleiadene, pyrene, and triphenylene. Unless statedotherwise specifically in the specification, the term “aryl” or theprefix “ar-” (such as in “aralkyl”) is meant to include aryl radicalsthat are optionally substituted.

“Aralkyl” refers to a radical of the formula —R_(b)—R_(c) where R_(b) isan alkylene chain as defined above and R_(c) is one or more arylradicals as defined above, for example, benzyl, diphenylmethyl and thelike. Unless stated otherwise specifically in the specification, anaralkyl group may be optionally substituted.

“Cycloalkyl” or “carbocyclic ring” refers to a stable non-aromaticmonocyclic or polycyclic hydrocarbon radical consisting solely of carbonand hydrogen atoms, which may include fused or bridged ring systems,having from three to fifteen carbon atoms, preferably having from threeto ten carbon atoms, and which is saturated or unsaturated and attachedto the rest of the molecule by a single bond. Monocyclic radicalsinclude, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example,adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl,and the like. Unless otherwise stated specifically in the specification,a cycloalkyl group may be optionally substituted.

“Cycloalkylalkyl” refers to a radical of the formula —R_(b)R_(d) whereR_(b) is an alkylene chain as defined above and R_(d) is a cycloalkylradical as defined above. Unless stated otherwise specifically in thespecification, a cycloalkylalkyl group may be optionally substituted.

“Cycloalkoxyalkyl” refers to a radical of the formula —R_(b)OR_(a) whereR_(a) is a cycloalkyl radical as defined above and R_(b) is an alkylradical as defined above containing one to twelve carbon atoms. Unlessstated otherwise specifically in the specification, an alkoxyalkyl groupmay be optionally substituted.

“Fused” refers to any ring structure described herein which is fused toan existing ring structure in the compounds of the invention. When thefused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atomon the existing ring structure which becomes part of the fusedheterocyclyl ring or the fused heteroaryl ring may be replaced with anitrogen atom.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and thelike. Unless stated otherwise specifically in the specification, ahaloalkyl group may be optionally substituted.

“Heterocyclyl” or “heterocyclic ring” refers to a stable 3- to18-membered non-aromatic ring radical which consists of two to twelvecarbon atoms and from one to six heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulfur. Unless stated otherwisespecifically in the specification, the heterocyclyl radical may be amonocyclic, bicyclic, tricyclic or tetracyclic ring system, which mayinclude fused or bridged ring systems; and the nitrogen, carbon orsulfur atoms in the heterocyclyl radical may be optionally oxidized; thenitrogen atom may be optionally quaternized; and the heterocyclylradical may be partially or fully saturated. Examples of suchheterocyclyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, Unless stated otherwise specifically in thespecification, a heterocyclyl group may be optionally substituted.

“N-heterocyclyl” refers to a heterocyclyl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heterocyclyl radical to the rest of the molecule is through anitrogen atom in the heterocyclyl radical. Unless stated otherwisespecifically in the specification, a N-heterocyclyl group may beoptionally substituted.

“Heterocyclylalkyl” refers to a radical of the formula —R_(b)R_(c) whereR_(b) is an alkylene chain as defined above and R_(c) is a heterocyclylradical as defined above, and if the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkyl radical at the nitrogen atom. Unless stated otherwisespecifically in the specification, a heterocyclylalkyl group may beoptionally substituted.

“Heteroaryl” refers to a 5- to 14-membered ring system radicalcomprising hydrogen atoms, one to thirteen carbon atoms, one to sixheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur, and at least one aromatic ring. For purposes of this invention,the heteroaryl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heteroarylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized. Examples include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][ 1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e. thienyl). Unless stated otherwisespecifically in the specification, a heteroaryl group may be optionallysubstituted.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. Unless stated otherwise specifically inthe specification, an N-heteroaryl group may be optionally substituted.

“Heteroarylalkyl” refers to a radical of the formula —R_(b)R_(f) whereR_(b) is an alkylene chain as defined above and R_(f) is a heteroarylradical as defined above. Unless stated otherwise specifically in thespecification, a heteroarylalkyl group may be optionally substituted.

“Amino acid ester” refers to an amino acid having an ester group inplace of the acid group. Unless stated otherwise specifically in thespecification, an amino acid ester group may be optionally substituted.

The term “substituted” used herein means any of the above groups (i.e.,alkyl, alkylene, alkoxy, alkoxyalkyl, alkylamino, alkylaminoalkyl,alkylsulfone, hydroxylalkyl, thioalkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, cycloalkoxyalkyl, haloalkyl, heterocyclyl,N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl,heteroarylalkyl and/or amino acid ester) wherein at least one hydrogenatom is replaced by a bond to a non-hydrogen atoms such as, but notlimited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom ingroups such as hydroxyl groups, alkoxy groups, and ester groups; asulfur atom in groups such as thiol groups, thioalkyl groups, sulfonegroups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groupssuch as amines, amides, alkylamines, dialkylamines, arylamines,alkylarylamines, diarylamines, N-oxides, imides, and enamines; a siliconatom in groups such as trialkylsilyl groups, dialkylarylsilyl groups,alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatomsin various other groups. “Substituted” also means any of the abovegroups in which one or more hydrogen atoms are replaced by ahigher-order bond (e.g., a double- or triple-bond) to a heteroatom suchas oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen ingroups such as imines, oximes, hydrazones, and nitriles. For example,“substituted” includes any of the above groups in which one or morehydrogen atoms are replaced with —NR_(g)R_(h), —NR_(g)C(═O)R_(h),—NR_(g)C(═O)NR_(g)R_(h), —NR_(g)C(═O)OR_(h), —NR_(g)SO₂R_(h),—OC(═O)NR_(g)R_(h), —OR_(g), —SR_(g), —SOR_(B), —SO₂R_(g), —OSO₂R_(g),—SO₂OR_(g), ═NSO₂R_(g), and —SO₂NR_(g)R_(h). “Substituted” also meansany of the above groups in which one or more hydrogen atoms are replacedwith —C(═O)R_(g), —C(═O)OR_(g), —C(═O)NR_(g)R_(h), —CH₂SO₂R_(g),—CH₂SO₂NR_(g)R_(h). In the foregoing, R_(g) and R_(h) are the same ordifferent and independently hydrogen, alkyl, alkoxy, alkylamino,thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl,heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl,N-heteroaryl and/or heteroarylalkyl. “Substituted” further means any ofthe above groups in which one or more hydrogen atoms are replaced by abond to an amino, alkylamino, cyano, hydroxyl, imino, nitro, oxo,thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl,heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkylgroup. In addition, each of the foregoing substituents may also beoptionally substituted with one or more of the above substituents.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound of the invention. Thus, the term “prodrug” refers to ametabolic precursor of a compound of the invention that ispharmaceutically acceptable. A prodrug may be inactive when administeredto a subject in need thereof, but is converted in vivo to an activecompound of the invention. Prodrugs are typically rapidly transformed invivo to yield the parent compound of the invention, for example, byhydrolysis in blood. The prodrug compound often offers advantages ofsolubility, tissue compatibility or delayed release in a mammalianorganism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24(Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi,T., et al., A.C.S. Symposium Series, Vol. 14, and in BioreversibleCarriers in Drug Design, Ed. Edward B. Roche, American PharmaceuticalAssociation and Pergamon Press, 1987.

The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound of the invention in vivowhen such prodrug is administered to a mammalian subject. Prodrugs of acompound of the invention may be prepared by modifying functional groupspresent in the compound of the invention in such a way that themodifications are cleaved, either in routine manipulation or in vivo, tothe parent compound of the invention. Prodrugs include compounds of theinvention wherein a hydroxy, amino or mercapto group is bonded to anygroup that, when the prodrug of the compound of the invention isadministered to a mammalian subject, cleaves to form a free hydroxy,free amino or free mercapto group, respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol or amide derivatives of amine functional groupsin the compounds of the invention and the like.

The invention disclosed herein is also meant to encompass allpharmaceutically acceptable compounds of structure (I) beingisotopically-labelled by having one or more atoms replaced by an atomhaving a different atomic mass or mass number. Examples of isotopes thatcan be incorporated into the disclosed compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P,³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. These radiolabelledcompounds could be useful to help determine or measure the effectivenessof the compounds, by characterizing, for example, the site or mode ofaction, or binding affinity to pharmacologically important site ofaction. Certain isotopically-labelled compounds of structure (I), forexample, those incorporating a radioactive isotope, are useful in drugand/or substrate tissue distribution studies. The radioactive isotopestritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful forthis purpose in view of their ease of incorporation and ready means ofdetection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundsof structure (I) can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed in the Preparations and Examples as set out below using anappropriate isotopically-labeled reagent in place of the non-labeledreagent previously employed.

The invention disclosed herein is also meant to encompass the in vivometabolic products of the disclosed compounds. Such products may resultfrom, for example, the oxidation, reduction, hydrolysis, amidation,esterification, and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising administering a compound of thisinvention to a mammal for a period of time sufficient to yield ametabolic product thereof. Such products are typically identified byadministering a radiolabelled compound of the invention in a detectabledose to an animal, such as rat, mouse, guinea pig, monkey, or to human,allowing sufficient time for metabolism to occur, and isolating itsconversion products from the urine, blood or other biological samples.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Mammal” includes humans and both domestic animals such as laboratoryanimals and household pets (e.g., cats, dogs, swine, cattle, sheep,goats, horses, rabbits), and non-domestic animals such as wildlife andthe like.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Pharmaceutically acceptable carrier, diluent or excipient” includeswithout limitation any adjuvant, carrier, excipient, glidant, sweeteningagent, diluent, preservative, dye/colorant, flavor enhancer, surfactant,wetting agent, dispersing agent, suspending agent, stabilizer, isotonicagent, solvent, or emulsifier which has been approved by the UnitedStates Food and Drug Administration as being acceptable for use inhumans or domestic animals.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as, but are not limited to,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, undecylenic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, deanol,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, benethamine, benzathine, ethylenediamine, glucosamine,methylglucamine, theobromine, triethanolamine, tromethamine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. Particularly preferred organic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, cholineand caffeine.

Often crystallizations produce a solvate of the compound of theinvention. As used herein, the term “solvate” refers to an aggregatethat comprises one or more molecules of a compound of the invention withone or more molecules of solvent. The solvent may be water, in whichcase the solvate may be a hydrate. Alternatively, the solvent may be anorganic solvent. Thus, the compounds of the present invention may existas a hydrate, including a monohydrate, dihydrate, hemihydrate,sesquihydrate, trihydrate, tetrahydrate and the like, as well as thecorresponding solvated forms. The compound of the invention may be truesolvates, while in other cases, the compound of the invention may merelyretain adventitious water or be a mixture of water plus someadventitious solvent.

A “pharmaceutical composition” refers to a formulation of a compound ofthe invention and a medium generally accepted in the art for thedelivery of the biologically active compound to mammals, e.g., humans.Such a medium includes all pharmaceutically acceptable carriers,diluents or excipients therefor.

“Effective amount” or “therapeutically effective amount” refers to thatamount of a compound of the invention which, when administered to amammal, preferably a human, is sufficient to effect treatment, asdefined below, of cancer in the mammal, preferably a human. The amountof a compound of the invention which constitutes a “therapeuticallyeffective amount” will vary depending on the compound, the condition andits severity, the manner of administration, and the age of the mammal tobe treated, but can be determined routinely by one of ordinary skill inthe art having regard to his own knowledge and to this disclosure.

“Treating” or “treatment” as used herein covers the treatment of thedisease or condition of interest in a mammal, preferably a human, havingthe disease or condition of interest, and includes:

(i) preventing the disease or condition from occurring in a mammal, inparticular, when such mammal is predisposed to the condition but has notyet been diagnosed as having it;

(ii) inhibiting the disease or condition, i.e., arresting itsdevelopment;

(iii) relieving the disease or condition, i.e., causing regression ofthe disease or condition; or

(iv) relieving the symptoms resulting from the disease or condition,i.e., relieving pain without addressing the underlying disease orcondition. As used herein, the terms “disease” and “condition” may beused interchangeably or may be different in that the particular maladyor condition may not have a known causative agent (so that etiology hasnot yet been worked out) and it is therefore not yet recognized as adisease but only as an undesirable condition or syndrome, wherein a moreor less specific set of symptoms have been identified by clinicians.

The compounds of the invention, or their pharmaceutically acceptablesalts or tautomers may contain one or more asymmetric centers and maythus give rise to enantiomers, diastereomers, and other stereoisomericforms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids. The present invention ismeant to include all such possible isomers, as well as their racemic andoptically pure forms. Optically active (+) and (−), (R)- and (S)-, or(D)- and (L)-isomers may be prepared using chiral synthons or chiralreagents, or resolved using conventional techniques, for example,chromatography and fractional crystallization. Conventional techniquesfor the preparation/isolation of individual enantiomers include chiralsynthesis from a suitable optically pure precursor or resolution of theracemate (or the racemate of a salt or derivative) using, for example,chiral high pressure liquid chromatography (HPLC). When the compoundsdescribed herein contain olefinic double bonds or other centres ofgeometric asymmetry, and unless specified otherwise, it is intended thatthe compounds include both E and Z geometric isomers. Likewise, alltautomeric forms are also intended to be included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule, for example, the conversion of aketone to an enol via a proton shift. The present invention includestautomers of any said compounds.

A “chemotherapeutic agent” is a chemical which eradicates, stops orslows the growth of cancer cells.

I. Compounds

As noted above, in one embodiment of the present invention, compoundshaving activity as PKM2 modulators (e.g., activators) are provided, thecompounds having the following structure (I):

or a stereoisomer, pharmaceutically acceptable salt, tautomer or prodrugthereof,

wherein:

-   -   R¹ is cycloalkyl, haloalkyl, halo, nitrile or amino;    -   R² is H or halo;    -   R³ is alkyl, alkoxyalkyl, cycloalkoxyalkyl, cycloalkyl,        cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,        heteroarylalkyl or aralkyl    -   R⁴ is aryl or heteroaryl    -   R⁵ and R⁶ are each independently H or alkyl.

In some embodiments, R⁴ is aryl. In other embodiments, R⁴ is heteroaryl.

In some more specific embodiments, R⁴ has one of the followingstructures (A), (B) or (C):

wherein:

H represents a 5 or 6-membered heterocyclic ring;

X is O, N, N⁺—O⁻ or S;

Y is CH or N;

R⁷ and R⁸ are each independently H, alkyl, alkoxy, halo, hydroxyl,hydroxylalkyl, amino, aminoalkyl, alkylaminoalkyl, nitrile, nitro,—O(CH₂)_(m)P(═O)(OH)₂, amino acid ester; and

m and n are each independently 0 or 1,

wherein all valences are satisfied.

In some embodiments of the foregoing, R⁴ has structure (A). For example,in some embodiments, R⁷ and R⁸ are each independently H, halo or amino.

In other embodiments. R⁴ has the following structure:

For example, in some embodiments R⁷ is H or amino, and in otherembodiments R⁸ is chloro or fluoro.

In some other more specific embodiments, R⁴ has one of the followingstructures:

In other embodiments, R⁴ has structure (B). For example, R⁴ has one ofthe following structures in certain embodiments:

In some of the above embodiments, R⁷ and R⁸ are each H, and in otherembodiments R⁷ or R⁸ is halo or alkylaminoalkyl.

In still other embodiments. R⁴ has one of the following structures.

In yet other exemplary embodiments, R⁴ has structure (C). For example,in some embodiments R⁴ has one of the following structures:

In some embodiments of the foregoing, R⁷ and R⁸ are each H. In otherembodiments, R⁷ or R⁸ is halo, amino or hydroxylalkyl.

In some other specific examples, R⁴ has one of the following structures:

In still other embodiments, R³ has one of the following structures (D),(E) or (F):

wherein:

Q is CH₂, O, NR¹³, CF₂, or S(O)_(w);

B is CH₂, O, NR¹⁴, C(═O) or

R⁹, R¹¹ and R¹³ are each independently H or alkyl;

R¹⁰ is H, H hydroxyl, halo, alkoxy or alkyl;

R¹² is H, H amino or alkoxy;

R¹⁴ is H, H alkyl or alkyl sulfone;

q, v and w are each independently 0, 1 or 2;

r and s are each independently 1 or 2;

t is 1, 2 or 3; and

u is 0, 1, 2 or 3.

In certain embodiments, R³ has structure (D).

In some embodiments, s is 1. In other embodiments, s is 2. In stillother embodiments, r is 1. In more other embodiments, r is 2. In somemore embodiments, q is 0. In yet other embodiments, q is 1. In otherembodiments, q is 2.

In some more specific examples, R³ has one of the following structures:

In some other embodiments, R³ has structure (E).

In some embodiments, Q is CH₂. In other embodiments, Q is SO₂. In moreembodiments, Q is O. In yet other embodiments, Q is CHF₂. In still otherembodiments, Q is NR¹³.

In some of the foregoing embodiments, R¹³ is methyl or ethyl.

In other of the foregoing embodiments, R¹⁰ and R¹¹ are each H. In yetother embodiments, R¹⁰ is methyl, fluoro, hydroxyl or methoxy.

In still other specific embodiments, R³ has one of the followingstructures:

In still other specific embodiments, R³ has structure (F). In some ofthese embodiments, B is CH₂. In other embodiments, R¹² is H. In someembodiments, R¹² is alkoxy. In still other embodiments, R¹² is methoxy,ethoxy or isopropoxy.

In some other exemplary embodiments, R³ has one of the followingstructures:

In still other embodiments, R³ is alkoxyalkyl, and in other embodimentsR³ is alkyl, for example, in some embodiments the alkyl is substitutedwith one or more substituents selected from hydroxyl, halo, amino,alkylamino, alkoxy and alkylsulfone. In other embodiments, R³ isheteroaryl. In yet other embodiments, R³ is cycloalkoxyalkyl. In moreembodiments, R³ is aralkyl.

In other embodiments, R⁵ and R⁶ are each H.

In some of any of the preceding embodiments, R² is H, and in otherembodiments R² is F.

In other embodiments of any of the foregoing embodiments, R¹ is CF₃. Inother embodiments, R¹ is Cl. In still other examples, R¹ is Br. In someembodiments, R¹ is cyclopropyl. In other embodiments, R¹ is nitrile. Inyet other embodiments, R¹ is amino.

In some embodiments of the compound of structure (I) the compound hasthe following structure (Ia′):

or a stereoisomer, pharmaceutically acceptable salt, tautomer or prodrugthereof,

wherein:

-   -   R⁷ and R⁸ are each independently H, alkyl, alkoxy, halo,        hydroxyl, hydroxylalkyl, amino, aminoalkyl, alkylaminoalkyl,        nitrile, nitro, —O(CH₂)_(m)P(═O)(OH)₂, amino acid ester; and    -   w is 1 or 2.

For example, in some embodiments of the compound of structure (I) thecompound has the following structure (Ia):

or a stereoisomer, pharmaceutically acceptable salt, tautomer or prodrugthereof,

wherein:

-   -   R¹⁵ is halo;    -   R¹⁶ is H or NH₂; and    -   w is 1 or 2.

In some embodiments of structure (Ia), R¹⁵ is chloro. In otherembodiments, R¹⁵ is fluoro.

In some other embodiments of structure (Ia), R¹⁶ is H. In otherembodiments, R¹⁶ is NH₂.

In still other embodiments of structure (Ia), w is 1. In otherembodiments, w is 2.

In other specific embodiments of structure (I), the compound has thefollowing structure (Ib′):

or a stereoisomer, pharmaceutically acceptable salt, tautomer or prodrugthereof,

wherein:

-   -   Q is CH₂, O, NR¹³, CF₂, or S(O)_(w);    -   R⁷ and R⁸ are each independently H, alkyl, alkoxy, halo,        hydroxyl, hydroxylalkyl, amino, aminoalkyl, alkylaminoalkyl,        nitrile, nitro, —O(CH₂)_(m)P(═O)(OH)₂, amino acid ester;    -   R⁹, R¹¹ and R¹³ are each independently H or alkyl;    -   R¹⁰ is H, hydroxyl, halo, alkoxy or alkyl;    -   w is 0, 1 or 2; and    -   t is 1, 2 or 3.

For example, in other specific embodiments of structure (I), thecompound has the following structure (Ib):

or a stereoisomer, pharmaceutically acceptable salt, tautomer or prodrugthereof,

wherein:

-   -   R¹⁷ is halo;    -   R¹⁸ is H or NH₂;    -   Z is CH₂, O, NH, NR¹⁹, CHR²⁰ or CF₂;    -   R¹⁹ is alkyl;    -   R²⁰ is alkoxy, hydroxyl or halo; and    -   x is 0, 1, 2 or 3.

For example, in some embodiments, R¹⁷ is chloro. In other embodiments,R¹⁸ is NH₂.

In still other embodiments of structure (Ib), Z is CHOH. In otherembodiments, Z is CHOCH₃. In more embodiments, Z is CHF, and in otherembodiments Z is O.

In more embodiments, x is 1, and in other embodiments x is 2.

In other exemplary embodiments of the compound of structure (I), thecompound has the following structure (IC):

or a stereoisomer, pharmaceutically acceptable salt, tautomer or prodrugthereof,

-   -   wherein:

B is CH₂, O, NR¹⁴, C(═O) or

-   -   R⁷ and R⁸ are each independently H, alkyl, alkoxy, halo,        hydroxyl, hydroxylalkyl, amino, aminoalkyl, alkylaminoalkyl,        nitrile, nitro, —O(CH₂)_(m)P(═O)(OH)₂, amino acid ester;    -   R¹² is H, amino or alkoxy;    -   v is 0, 1 or 2; and    -   u is 0, 1,2 or 3.

For example, in other exemplary embodiments of the compound of structure(I), the compound has the following structure (Ic):

or a stereoisomer, pharmaceutically acceptable salt, tautomer or prodrugthereof,

wherein:

-   -   R²¹ and R²² are each independently H or halo;    -   R²³ is H or alkyl; and    -   y is 1 or 2.

In some embodiments, R²¹ is chloro. In other embodiments, R²¹ is F.

In still other embodiments, R²² is H. In other embodiments, R²³ ismethyl, ethyl or isopropyl.

In certain exemplary embodiments, y is 1. In other embodiments, y is 2.

In other certain embodiments, the compound is selected from a compoundin Table 1.

TABLE 1 Exemplary Compounds PKM₂ AC₅₀ ES-MS (nM)/Max. EX Structure NMR(M⁺ + 1) Resp.* (%) Note^(†)  1

¹H-NMR (CDCl₃/400 MHz): 7.10 (m, 1H), 6.80 (m, 1H), 6.59 (d, J = 8.4 Hz,1H), 6.52 (d, J = 12.0 Hz, 1H), 4.69 (s, 2H), 3.50 (s, 2H), 2.65 (m,1H), 2.00-1.58 (m, 6H). 372.1      11/100 —  2

¹H-NMR (CD₃OD/ 400 MHz): 7.31 (m, 1H), 7.00 (m, 3H), 4.80 (m, 2H), 3.56(m, 2H), 2.66 (m, 1H), 2.00-1.59 (m, 6H). 410.9     3788/39 —  3

¹H-NMR (CD₃OD/ 400 MHz): 7.08 (m, 1H), 6.54 (m, 2H), 5.70 (m, 1H), 4.63(m, 2H), 3.64 (m, 1H), 3.56 (m, 1H), 2.64 (m, 1H), 2.01- 1.58 (m, 6H).319.0     43850/45 —  4

¹H-NMR (CD₃OD/ 400 MHz): 7.34 (m, 5H), 6.60 (s, 1H), 5.60 (m, 1H), 4.80(m, 1H), 3.40 (m, 2H), 2.40 (m, 1H), 2.01-1.58 (m, 6H). 361.9    1482/52 —  5

¹H-NMR (CD₃OD/ 400 MHz): 7.40 (m, 5H), 6.80 (s, 1H), 5.48 (m, 2H), 3.50(m, 2H), 2.34 (m, 1H), 2.01-1.58 (m, 6H). 352.0     4651/106 —  6

¹H-NMR (CDCl₃/400 MHz; stable amide rotamers were observed by NMR): 7.35(m, 1H), 7.24 (br, 1H), 7.10 (m, 1H), 6.97 (m, 0.5H), 6.84 (m, 1H), 6.60(m, 0.5H), 6.50 (m, 0.5H), 6.39 (m, 0.5H), 5.05 (s, 2H), 3.60 (s, 1H),3.34 (s, 1H), 2.74 (m, 1H), 2.50-1.55 (m, 6H). 377.0      213/100 —  7

¹H-NMR (CD₃OD/ 400 MHz): 7.31 (m, 1H), 7.04 (m, 3H), 5.04 (m, 1H), 5.04(m, 1H), 3.70 (m, 1H), 3.50 (m, 1H), 2.56 (m, 1H), 2.00- 1.56 (m, 6H).368.0     3446/87 —  8

¹H-NMR (CD₃OD/ 400 MHz): 7.05 (m, 2H), 6.54 (m, 2H), 4.68 (m, 2H), 3.67(m, 1H), 3.46 (m, 1H), 2.67 (m, 1H), 2.01-1.62 (m, 6H). 328.9 NA —  9

¹H-NMR (CD₃OD/400 MHz): 7.30 (m, 1H), 7.10 (m, 2H), 6.50 (m, 1H), 4.77(m, 2H), 3.53 (m, 2H), 2.66 (m, 1H), 2.00-1.59 (m, 6H). 377.0    15400/80 —  10

¹H-NMR (CD₃OD/ 400 MHz): 7.30 (m, 1H), 7.06 (m, 2H), 6.50 (m, 1H), 4.77(m, 2H), 3.53 (m, 2H), 2.66 (m, 1H), 2.00-1.59 (m, 6H). 420.9    2740/127 —  11

¹H-NMR (CD₃OD/400 MHz): 7.06 (m, 1H), 6.60 (m, 3H), 4.80 (m, 2H), 4.00(m, 4H), 3.75 (m, 2H), 3.10 (m, 1H). 382.9     10400/61 —  12

¹H-NMR (CD₃OD/400 MHz): 7.38 (m, 1H), 7.29 (m, 1H), 7.12 (m, 1H), 6.90(m, 1H), 6.67 (m, 1H), 6.40 (m, 1H), 5.07 (m, 2H), 4.57 (m, 2H), 4.37(m, 2H), 4.08 (m, 1H), 3.86 (m, 2H). 378.9     3271/101 —  13

¹H-NMR (CD₃OD/400 MHz): 7.33 (m, 1H), 7.27 (m, 1H), 7.07 (m, 1H), 6.73(m, 2H), 6.36 (m, 1H), 6.40 (m, 1H), 5.17 (m, 2H), 3.42 (m, 2H), 1.02(s, 9H). 379.0     49110/33 —  14

¹H-NMR (CD₃OD/400 MHz): 7.37 (m, 2H), 6.95 (m, 1H), 6.55 (m, 1H), 4.60(m, 2H), 3.80 (m, 2H), 3.60 (m, 2H), 3.30 (m, 2H), 2.70 (m, 1H),2.03-1.50 (m, 6H). 379.0     1700/81 —  15

¹H-NMR (CD₃OD/400 MHz): 7.01 (m, 1H), 6.82 (m, 1H), 6.60 (m, 1H), 6.54(m, 1H), 4.88 (m, 2H), 4.67 (m, 4H), 4.44 (m, 2H), 3.78 (m, 1H). 373.9     150/102 —  16

¹H-NMR (CD₃OD/400 MHz): 7.32 (m, 5H), 6.80 (m, 1H), 4.78 (m, 2H), 3.77(m, 1H), 1.29 (m, 4H), 1.20 (m, 3H), 0.89 (m, 3H). 340.0     74820/22 — 17

¹H-NMR (CD₃OD/400 MHz): 7.25 (m, 4H), 6.83 (m, 1H), 4.80 (m, 2H), 3.40(m, 2H), 1.62 (m, 2H), 1.29 (m, 4H), 0.87 (m, 3H). 350.7      138/83 — 18

¹H-NMR (CD₃OD/400 MHz): 8.19 (m, 1H), 6.80 (m, 1H), 6.55 (m, 1H), 4.70(m, 2H), 4.30 (m, 4H), 3.87 (m, 1H), 3.34 (m, 2H). 356.9 NA —  19

¹H-NMR (CD₃OD/400 MHz): 7.34 (m, 5H), 6.80 (m, 1H), 4.77 (m, 2H), 3.47(m, 2H), 1.62 (m, 2H), 1.23 (m, 4H), 0.89 (m, 3H). 340.0      920/76 — 20

¹H-NMR (CD₃OD/400 MHz): 7.31 (m, 1H), 7.12 (m, 4H), 4.88 (m, 2H), 4.67(m, 4H), 4.40 (m, 2H), 3.83 (m, 1H). 358.1     12000/70 —  21

¹H-NMR (CD₃OD/400 MHz): 7.28 (m, 1H), 7.14 (m, 2H), 6.56 (m, 1H), 3.93(m, 3H), 3.80 (m, 2H), 3.40 (m, 2H), 2.77 (m, 1H), 1.89 (m, 2H), 1.44(m, 2H). 388.5 >10000 —  22

¹H-NMR (CD₃OD/400 MHz): 7.38 (m, 2H), 7.14 (m, 3H), 3.95 (m, 2H), 3.40(m, 2H), 3.40 (m, 3H), 1.95 (m, 2H), 1.86 (m, 2H), 1.10 (m, 2H). 388.5    1516/99 —  23

¹H-NMR (CD₃OD/400 MHz): 7.35 (m, 2H), 7.15 (m, 2H), 7.15 (m, 2H), 6.86(m, 1H), 4.89 (s, 2H), 3.65 (m, 2H), 3.36 (m, 2H), 3.26 (m, 2H), 1.89(m, 3H 360.4     7540/75 —  24

¹H-NMR (CD₃OD/400 MHz): 7.11 (m, 2H), 6.55 (m, 2H), 4.76 (m, 2H), 3.67(m, 4H), 3.31 (m, 2H), 1.16 (m, 3H). 376.4      210/100 —  25

¹H-NMR (CD₃OD/400 MHz): 7.84 (m, 1H), 7.47 (m, 1H), 7.34 (m, 1H), 7.21(m, 1H), 7.13 (m, 2H), 7.02 (m, 2H), 4.78 (m, 2H). 355.4     53000/35 — 26

¹H-NMR (CD₃OD/400 MHz): 7.40 (m, 2H), 7.15 (m, 2H), 7.84 (m, 1H), 4.90(m, 2H), 3.78 (m, 4H), 3.32 (m, 2H), 2.07 (m, 2H), 1.69 (m, 2H), 1.50(m, 1H). 386.4      377/99 —  27

¹H-NMR (DMSO- d₆/400 MHz): 7.50 (m, 1H), 7.34 (m, 3H), 7.21 (m, 1H),4.75 (m, 2H), 4.55 (m, 2H), 3.50 (m, 4H), 3.20 (m, 1H). 374.4    33000/47 —  28

¹H-NMR (DMSO- d₆/400 MHz): 7.92 (m, 1H), 7.72 (m, 2H), 7.60 (m, 1H),7.51 (m, 2H), 5.00 (m, 2H), 4.65 (m, 2H), 4.40 (m, 4H), 3.20 (m, 1H).365.4 NA —  29

¹H-NMR (CD₃OD/400 MHz): 7.45 (m, 1H), 7.20 (m, 4H), 5.00 (m, 2H), 3.60(m, 4H), 3.32 (m, 2H), 1.15 (m, 3H). 376.4     4640/87 —  30

¹H-NMR (CD₃OD/400 MHz): 7.38 (m, 2H), 7.13 (m, 3H), 4.85 (m, 2H), 3.76(m, 2H), 3.47 (s, 2H), 3.43 (m, 2H), 1.49 (m, 3H). 360.4     9770/72 — 31

¹H-NMR (CD₃OD/400 MHz): 7.43 (m, 1H), 7.29 (m, 4H), 4.91 (m, 2H), 3.70(m, 2H), 3.54 (m, 2H), 3.44 (m, 2H), 3.37 (m, 2H), 3.32 (s, 3H). 376.4    9590/82 —  32

¹H-NMR (CD₃OD/400 MHz): 7.03 (m, 4H), 6.50 (m, 1H), 4.63 (m, 2H), 3.57(m, 2H), 3.10 (m, 2H), 3.02 (m, 2H), 1.30 (m, 4H), 1.15 (m, 3H). 416.4    1002/107 —  33

¹H-NMR (CD₃OD/400 MHz): 7.45 (m, 2H), 7.35 (m, 1H), 6.95 (m, 1H), 5.19(m, 2H), 3.69 (m, 4H), 3.20 (m, 2H), 1.87 (m, 2H), 1.60 (m, 3H). 436.4    4026/81 —  34

¹H-NMR (CD₃OD/400 MHz): 7.15 (m, 1H), 7.02 (m, 1H), 6.58 (m, 1H), 6.52(m, 1H), 4.74 (m, 2H), 3.77 (m, 4H), 3.44 (m, 2H), 2.14 (m, 2H), 1.64(m, 3H). 402.4      77/109 —  35

¹H-NMR (CD₃OD/400 MHz): 7.44 (m, 1H), 7.31 (m, 4H), 4.90 (m, 2H), 3.92(m, 2H), 3.50 (m, 3H), 1.85 (m, 2H), 1.75 (m, 2H). 388.4     5080/59 — 36

¹H-NMR (CD₃OD/400 MHz): 7.44 (m, 1H), 7.32 (m, 3H), 6.80 (m, 1H), 4.91(m, 2H), 3.68 (m, 2H), 3.47 (m, 2H), 3.11 (m, 2H), 1.45 (m, 7H). 416.4    1218/88 —  37

¹H-NMR (DMSO- d₆/400 MHz): 8.27 (m, 1H), 8.13 (m, 4H), 5.62 (m, 2H),4.16 (m, 2H), 4.32 (m, 2H), 4.25 (m, 1H), 1.82 (d, 6H). 390.3    42000/37 —  38

¹H-NMR (CD₃OD/400 MHz): 7.42 (m, 1H), 7.29 (m, 4H), 4.89 (m, 2H), 3.50(m, 2H), 3.41 (m, 4H), 1.92 (m, 2H), 1.12 (t, 6H). 390.3     33000/47 — 39

¹H-NMR (CD₃OD/400 MHz): 7.32 (m, 2H), 7.15 (m, 3H), 4.81 (m, 2H), 3.80(m, 3H), 3.41 (m, 4H), 1.60 (m, 8H). 400.5     47000/30 —  40

¹H-NMR (CD₃OD/400 MHz): 7.41 (m, 1H), 7.00 (m, 3H), 4.88 (m, 2H), 3.70(m, 4H), 3.40 (m, 2H), 2.05 (m, 2H), 1.62 (m, 2H), 1.40 (m, 1H). 404.4    1171/114 —  41

¹H-NMR (CD₃CN/400 MHz): 7.35 (m, 2H), 7.17 (m, 2H), 6.90 (m, 1H), 4.80(d, 2H), 3.82 (m, 2H), 3.53 (m, 2H), 3.26 (m, 2H), 1.53 (m, 5H), 1.16(m, 2H). 400.4     1258/118 —  42

¹H-NMR (CD₃OD/400 MHz): 7.44 (d, 2H), 7.34 (t, 1H), 7.01 (m, 1H), 5.16(m, 2H), 3.60 (m, 2H), 3.40 (m, 4H), 1.10 (m, 3H). 410.4     8780/76 — 43

¹H-NMR (CD₃OD/400 MHz): 7.46 (m, 1H), 7.20 (m, 3H), 6.88 (m, 1H), 4.85(m, 2H), 3.80 (m, 2H), 3.60 (m, 1H), 3.48 (m, 2H), 3.25 (m, 1H), 2.01(m, 2H), 1.70 (m, 2H), 1.45 (m, 1H). 402.4     1330/110 —  44

¹H-NMR (CD₃OD/400 MHz): 7.45 (m, 1H), 7.29 (m, 4H), 4.83 (m, 2H), 3.80(m, 2H), 3.36 (m, 3H), 1.80 (m, 4H), 1.47 (m, 4H). 416.4     50000/32 — 45

¹H-NMR (Acetone- d₆/400 MHz): 7.40 (m, 2H), 7.28 (m, 3H), 4.98 (d, 2H),3.84 (m, 2H), 3.61 (m, 1H), 3.40 (m, 1H), 3.28 (m, 2H), 2.08 (m, 1H),1.63 (m, 2H), 1.30 (m, 2H). 386.4     25150/52 —  46

¹H-NMR (CD₃CN/400 MHz): 7.28 (m, 2H), 7.16 (m, 3H), 4.80 (d, 2H), 3.80(m, 2H), 3.60 (m, 3H), 1.95 (m, 1H), 1.80 (m, 4H), 1.41 (m, 1H). 386.4    13410/70 —  47

¹H-NMR (CD₃OD/400 MHz): 7.33 (m, 2H), 7.12 (m, 2H), 6.90 (m, 1H), 4.81(m, 2H), 4.20 (m, 1H), 3.14 (m, 1H), 2.09 (m, 2H), 1.82 (m, 2H), 1.66(m, 2H), 1.21 (m, 2H). 400.4      435/89 —  48

¹H-NMR (CD₃OD/400 MHz): 7.33 (m, 1H), 7.00 (m, 4H), 4.80 (m, 2H), 4.20(m, 1H), 3.28 (s, 3H), 3.12 (m, 1H), 2.07 (m, 2H), 1.80 (m, 2H), 1.70(m, 2H), 1.23 (m, 2H). 400.4     8580/80 —  49

¹H-NMR (Acetone- d₆/400 MHz): 7.40 (m, 1H), 7.00 (m, 3H), 4.92 (m, 2H),3.24 (s, 3H), 3.00 (m, 2H), 1.76 (m, 4H), 1.15 (m, 4H). 418.4     914/122 —  50

¹H-NMR (Acetone- d₆/400 MHz): 7.17 (m, 2H), 7.07 (m, 2H), 4.90 (m, 2H),4.15 (m, 1H), 3.24 (s, 3H), 3.05 (m, 3H), 1.96 (m, 2H), 1.80 (m, 2H),1.24 (m, 2H). 418.4     1667/90 —  51

¹H-NMR (Acetone- d₆/400 MHz): 7.03 (m, 3H), 6.89 (m, 1H), 4.80 (m, 2H),4.32 (m, 1H), 3.25 (s, 3H), 3.05 (m, 3H), 1.96 (m, 2H), 1.80 (m, 2H),1.20 (m, 2H). 418.4     50380/31 —  52

¹H-NMR (CD₃OD/400 MHz): 7.40 (m, 1H), 7.30 (m, 4H), 4.81 (m, 2H), 3.29(s, 3H), 3.13 (m, 2H), 2.10 (m, 2H), 1.85 (m, 2H), 1.62 (m, 2H), 1.23(m, 2H). 416.4      879/100 —  53

¹H-NMR (CD₃OD/400 MHz): 7.40 (m, 1H), 7.30 (m, 4H), 4.79 (m, 2H), 3.79(m, 2H), 2.00 (m, 2H), 1.85 (m, 2H), 1.63 (m, 2H), 1.22 (m, 2H), 1.10(d, 6H). 444.4     2287/63 —  54

¹H-NMR (CD₃OD/400 MHz): 7.45 (m, 1H), 7.27 (m, 3H), 6.80 (m, 1H), 4.80(m, 2H), 4.22 (m, 1H), 3.25 (s, 3H), 3.05 (m, 1H), 2.05 (m, 2H), 1.84(m, 2H), 1.66 (m, 2H), 1.20 (m, 2H). 397.5      365/93 TFA  55

¹H-NMR (CD₃OD/400 MHz): 7.30 (m, 2H), 7.08 (m, 3H), 4.78 (m, 2H), 4.20(m, 1H), 3.50 (m, 2H), 3.20 (m, 1H), 2.05 (m, 2H), 1.80 (m, 2H), 1.70(m, 2H), 1.20 (m, 2H), 1.12 (t, 3H). 414.4      469/101 —  56

¹H-NMR (Acetone- d₆/400 MHz): 8.53 (m, 1H), 7.86 (m, 1H), 7.37 (m, 1H),6.63 (m, 1H), 5.00 (m, 2H), 4.20 (m, 1H), 3.25 (s, 3H), 3.08 (m, 1H),1.95 (m, 4H), 1.42 (m, 2H), 1.26 (m, 2H). 417.4     2580/48 TFA  57

¹H-NMR (dmso- d₆/400 MHz): 7.06 (m, 1H), 6.54 (m, 2H), 6.30 (m, 1H),4.54 (m, 2H), 4.10 (m, 1H), 3.20 (s, 3H), 3.00 (m, 1H), 1.95 (m, 2H),1.70 (m, 2H), 1.50 (m, 4H), 1.15 (m, 2H). 431.4 TBD TFA  58

¹H-NMR (CD₃OD/400 MHz): 7.10 (m, 1H), 6.89 (m, 1H), 6.71 (m, 1H), 6.38(m, 1H), 4.75 (m, 2H), 4.31 (m, 1H), 3.20 (s, 3H), 3.10 (m, 1H), 2.10(m, 2H), 1.90 (m, 2H), 1.65 (m, 2H), 1.28 (m, 2H). 431.4 TBD TFA  59

¹H-NMR (CD₃CN/400 MHz): 7.35 (m, 2H), 7.16 (m, 2H), 6.80 (m, 1H), 4.77(m, 2H), 3.85 (m, 4H), 3.52 (m, 2H), 2.30 (m, 2H), 1.62 (m, 5H), 1.17(m, 4H). 456.5      494/100 —  60

¹H-NMR (CDCl₃/400 MHz): 7.35 (m, 1H), 7.18 (m, 3H), 6.70 (m, 1H), 4.87(m, 2H), 3.59 (m, 2H), 2.28 (m, 4H), 2.04 (m, 2H), 1.70 (m, 3H), 1.44(m, 2H). 412.5      101/105 —  61

¹H-NMR (DMSO- d₆/400 MHz): 7.32 (m, 1H), 7.20 (m, 4H), 4.73 (m, 2H),3.30 (m, 2H), 3.13 (m, 2H), 2.93 (s, 3H), 1.99 (m, 2H). 408.4 NA —  62

¹H-NMR (DMSO- d₆/400 MHz): 7.46 (m, 1H), 7.35 (m, 3H), 6.85 (m, 1H),4.91 (m, 2H), 3.60 (m, 2H), 3.10 (m, 2H), 2.72 (m, 1H), 2.41 (m, 2H),1.85 (m, 2H). 450.4      273/105 —  63

¹H-NMR (CD₃OD/400 MHz): 7.36 (m, 2H), 7.15 (m, 2H), 6.85 (m, 1H), 4.92(m, 2H), 3.50 (m, 2H), 3.12 (m, 2H), 3.00 (m, 1H), 2.71 (m, 2H), 2.24(m, 2H), 1.85 (m, 2H). 434.4      240/87 —  64

¹H-NMR (DMSO- d₆/400 MHz): 7.52 (m, 2H), 7.35 (m, 1H), 7.38 (m, 1H),5.03 (m, 2H), 3.50 (m, 2H), 3.12 (m, 2H), 2.92 (m, 3H), 2.16 (m, 2H),1.65 (m, 2H). 484.3     3780/71 —  65

¹H-NMR (CD₃OD/400 MHz): 7.47 (m, 1H), 7.37 (m, 3H), 6.80 (m, 1H), 4.97(m, 2H), 3.90 (m, 2H), 3.42 (m, 2H), 3.12 (m, 2H), 1.33 (m, 3H). 424.3NA —  66

¹H-NMR (CD₃OD/400 MHz): 7.41 (m, 1H), 7.00 (m, 3H), 5.01 (m, 2H), 3.58(m, 2H), 3.10 (m, 2H), 2.65 (m, 1H), 2.35 (m, 2H), 1.77 (m, 4H). 452.4     375/102 —  67

¹H-NMR (CD₃OD/400 MHz): 7.39 (m, 1H), 7.02 (m, 3H), 6.90 (m, 1H), 4.80(m, 2H), 3.60 (m, 3H), 3.20 (m, 3H), 2.99 (m, 2H), 2.30 (m, 3H). 434.4    1626/95 —  68

¹H-NMR (Acetone- d₆/400 MHz): 7.20 (m, 4H), 4.98 (d, 2H), 3.61 (m, 2H),3.20 (m, 2H), 3.00 (m, 2H), 2.60 (m, 1H), 2.45 (m, 2H), 1.80 (m, 2H).452.4      766/103 —  69

¹H-NMR (Acetone- d₆/400 MHz): 7.00 (m, 4H), 4.90 (d, 2H), 3.61 (m, 2H),3.20 (m, 2H), 3.00 (m, 2H), 2.60 (m, 1H), 2.45 (m, 2H), 1.80 (m, 2H).452.4     1835/74 —  70

¹H-NMR (Acetone- d₆/400 MHz): 7.20 (m, 4H), 4.90 (d, 2H), 3.61 (m, 2H),3.20 (m, 2H), 3.00 (m, 2H), 2.60 (m, 1H), 2.45 (m, 2H), 1.80 (m, 2H).452.4      884/91 —  71

¹H-NMR (Acetone- d₆/400 MHz): 7.30 (m, 2H), 7.18 (m, 2H), 7.00 (m, 1H),4.90 (d, 2H), 3.61 (m, 2H), 3.00 (m, 4H), 2.25 (m, 1H), 2.15 (m, 2H),1.87 (m, 2H). 434.4     10200/71 —  72

¹H-NMR (Acetone- d₆/400 MHz): 7.36 (m, 4H), 7.00 (m, 1H), 4.95 (d, 2H),3.61 (m, 2H), 3.00 (m, 4H), 2.25 (m, 1H), 2.15 (m, 2H), 1.87 (m, 2H).450.4     19660/22 —  73

¹H-NMR (Acetone- d₆/400 MHz): 7.41 (m, 4H), 6.80 (m, 1H), 4.95 (d, 2H),3.61 (d, 2H), 2.60 (m, 4H), 1.99 (m, 1H), 1.61 (m, 2H), 1.30 (m, 4H).432.4     1343/79 —  74

¹H-NMR (Acetone- d₆/400 MHz): 7.41 (m, 4H), 6.90 (m, 1H), 4.95 (d, 2H),3.61 (d, 2H), 3.16 (m, 2H), 2.81 (m, 1H), 2.53 (m, 2H), 2.08 (m, 2H),1.73 (m, 4H). 448.4      640/95 —  75

¹H-NMR (CD₃CN/400 MHz): 7.47 (m, 1H), 7.32 (m, 3H), 6.90 (m, 1H), 4.85(m, 2H), 3.49 (m, 2H), 2.90 (m, 4H), 2.25 (m, 2H), 2.05 (m, 1H), 1.61(m, 4H). 464.4      188/102 —  76

¹H-NMR (CD₃CN/400 MHz): 7.15 (m, 1H), 6.80 (m, 1H), 6.60 (m, 2H), 4.72(m, 2H), 3.50 (m, 2H), 3.19 (m, 2H), 2.95 (m, 1H), 2.55 (m, 1H), 2.35(m, 2H), 1.80 (m, 3H). 450.4      54/93 —  77

¹H-NMR (CD₃CN/400 MHz): 7.40 (m, 1H), 7.15 (m, 2H), 6.95 (m, 1H), 6.75(m, 2H), 5.65 (s, 1H), 5.38 (s, 1H), 3.48 (m, 2H), 3.40 (m, 1H), 3.05(m, 1H), 3.00 (m, 1H), 2.45 (m, 2H), 1.75 (m, 4H). 431.4     34820/43 — 78

¹H-NMR (CD₃CN/400 MHz): 7.47 (m, 2H), 7.18 (m, 2H), 6.90 (m, 1H), 4.85(d, 2H), 3.59 (d, 2H), 2.90 (m, 4H), 2.05 (m, 1H), 2.70 (m, 6H). 448.4     485/102 —  79

¹H-NMR (Acetone- d₆/400 MHz): 7.21 (m, 5H), 4.70 (d, 2H), 3.40 (d, 2H),2.47 (m, 2H), 1.86 (m, 1H), 1.70 (m, 2H), 1.41 (m, 2H), 1.14 (m, 4H).416.4     1193/95 —  80

¹H-NMR (Acetone- d₆/400 MHz): 7.35 (m, 1H), 7.18 (m, 2H), 4.70 (d, 2H),3.60 (d, 2H), 2.60 (m, 2H), 2.50 (m, 2H), 2.00 (m, 2H), 1.61 (m, 2H),1.27 (m, 3H). 382.4     1301/46 —  81

¹H-NMR (CD₃CN/400 MHz): 7.36 (m, 2H), 7.17 (m, 2H), 6.60 (m, 1H), 4.90(d, 2H), 3.63 (d, 2H), 3.01 (m, 4H), 2.18 (m, 3H), 1.70 (m, 4H). 414.4    1366/72 —  82

¹H-NMR (Acetone- d₆/400 MHz): 7.35 (m, 2H), 7.15 (m, 2H), 6.55 (m, 1H),4.90 (d, 2H), 3.60 (d, 2H), 2.60 (m, 4H), 2.00 (m, 2H), 1.60 (m, 2H),1.25 (m, 3H). 426.4     1372/74 —  83

¹H-NMR (CD₃CN/400 MHz): 7.36 (m, 2H), 7.18 (m, 2H), 6.60 (m, 1H), 4.90(d, 2H), 3.60 (d, 2H), 2.98 (m, 4H), 2.19 (m, 2H), 1.71 (m, 5H). 458.4    1104/98 —  84

¹H-NMR (ACN- d₃/400 MHz): 7.40 (m, 1H), 7.02 (m, 2H), 6.98 (m, 1H), 4.83(m, 2H), 3.35 (m, 2H), 2.51 (m, 4H), 2.17 (m, 2H), 1.90 (m, 2H), 1.48(m, 2H), 1.21 (m, 3H). 434.4      697/73 —  85

¹H-NMR (CD₃CN/400 MHz): 7.36 (m, 2H), 7.05 (m, 3H), 5.00 (m, 2H), 3.60(m, 2H), 2.99 (m, 4H), 2.90 (m, 2H), 1.68 (m, 5H), 2.98 (m, 4H). 466.4     64/100 —  86

¹H-NMR (Acetone- d₆/400 MHz): 7.22 (m, 1H), 7.00 (m, 1H), 6.63 (m, 2H),4.75 (m, 2H), 3.40 (m, 2H), 2.60 (m, 4H), 2.00 (m, 2H), 1.55 (m, 2H),1.25 (m, 3H). 432.4      93/98 —  87

¹H-NMR (CD₃CN/400 MHz): 7.15 (m, 1H), 6.84 (m, 1H), 6.63 (m, 2H), 4.72(m, 2H), 3.44 (m, 2H), 2.92 (m, 4H), 2.04 (m, 2H), 1.60 (m, 5H). 464.4     64/100 —  88

¹H-NMR (CD₃OD/400 MHz): 8.77 (m, 1H), 7.98 (m, 1H), 7.60 (m, 2H), 6.97(m, 1H), 5.00 (m, 2H), 3.60 (m, 2H), 3.20 (m, 2H), 2.40 (m, 2H), 1.84(m, 3H). 417.4     3600/96 TFA  89

¹H-NMR (CD₃OD/400 MHz): 8.80 (m, 1H), 7.90 (m, 3H), 6.97 (m, 1H), 5.10(m, 2H), 3.85 (m, 2H), 3.20 (m, 2H), 2.80 (m, 2H), 2.40 (m, 2H), 1.90(m, 3H). 417.4     58000/35 TFA  90

¹H-NMR (CD₃OD/400 MHz): 8.70 (m, 2H), 8.27 (m, 1H), 7.91 (m, 1H), 4.84(m, 2H), 3.64 (m, 2H), 3.10 (m, 2H), 2.65 (m, 1H), 2.30 (m, 2H), 1.80(m, 4H). 417.4     52000/24 TFA  91

¹H-NMR (CD₃OD/400 MHz): 7.09 (m, 1H), 6.90 (m, 1H), 6.52 (m, 1H), 6.41(m, 1H), 4.84 (m, 2H), 3.50 (m, 4H), 2.80 (m, 5H), 1.55 (m, 4H). 463.4     58/78 TFA  92

¹H-NMR (Acetone- d₆/400 MHz): 8.50 (m, 1H), 7.92 (m, 1H), 7.42 (m, 2H),6.76 (m, 1H), 5.11 (m, 2H), 3.64 (m, 2H), 3.10 (m, 2H), 2.65 (m, 1H),2.30 (m, 2H), 1.80 (m, 4H). 451.4     1290/74 TFA  93

¹H-NMR (Acetone- d₆/400 MHz): 8.94 (m, 1H), 7.90 (m, 1H), 7.05 (m, 1H),5.10 (m, 2H), 3.75 (m, 2H), 3.20 (m, 2H), 2.90 (m, 1H), 2.70 (m, 1H),2.40 (m, 2H), 1.80 (m, 3H). 423.6     49000/26 —  94

¹H-NMR (CDCl₃/400 MHz): 7.83 (m, 1H), 7.46 (m, 2H), 6.50 (m, 1H), 5.10(m, 2H), 3.60 (m, 2H), 3.20 (m, 2H), 3.00 (m, 1H), 2.90 (m, 1H), 2.70(m, 1H), 2.40 (m, 2H), 1.88 (m, 3H). 495.4     2380/69 —  95

¹H-NMR (CD₃CN/400 MHz): 7.17 (m, 1H), 6.64 (m, 2H), 6.52 (m, 1H), 4.62(m, 2H), 3.49 (m, 1H), 3.30 (m, 1H), 3.10 (m, 2H), 2.90 (m, 1H), 2.70(m, 1H), 2.20 (m, 2H), 1.73 (m, 3H). 465.4 TBD TFA  96

¹H-NMR (CD₃CN/400 MHz): 7.06 (m, 1H), 6.80 (m, 1H), 6.56 (m, 1H), 6.47(m, 1H), 4.77 (m, 2H), 3.50 (m, 2H), 3.10 (m, 2H), 2.90 (m, 1H), 2.80(m, 1H), 2.60 (m, 1H), 2.30 (m, 2H), 1.80 (m, 3H). 465.4 TBD TFA  97

¹H-NMR (CD₃CN/400 MHz): 7.96 (m, 1H), 7.60 (m, 2H), 7.10 (m, 1H), 5.34(m, 2H), 4.10 (m, 2H), 3.59 (m, 4H), 2.50 (m, 2H), 2.17 (m, 5H). 479.4TBD TFA  98

¹H-NMR (Acetone- d₆/400 MHz): 7.37 (m, 2H), 7.13 (m, 2H), 7.00 (m, 1H),5.00 (m, 2H), 3.62 (m, 4H), 3.00 (m, 2H), 1.55 (m, 7H). 399.4    2050/56 TFA  99

¹H-NMR (CDCl₃/400 MHz): 7.35 (m, 2H), 7.16 (m, 2H), 6.66 (m, 1H), 4.87(m, 2H), 3.77 (m, 2H), 3.53 (m, 2H), 2.74 (s, 3H), 2.61 (m, 2H), 1.60(m, 4H), 1.36 (m, 3H). 477.5      110/100 — 100

¹H-NMR (DMSO- d₆/400 MHz): 9.32 (m, 1H), 7.43 (m, 1H), 7.20 (m, 3H),6.94 (m, 1H), 4.80 (m, 2H), 3.40 (m, 4H), 2.90 (m, 5H), 1.90 (m, 3H),1.40 (m, 2H). 399.5    101000/29 TFA 101

¹H-NMR (DMSO- d₆/400 MHz): 7.92 (m, 1H), 7.72 (m, 2H), 7.60 (m, 1H),7.51 (m, 2H), 5.00 (m, 2H), 4.65 (m, 2H), 4.40 (m, 4H), 3.20 (m, 1H).365.4     1856/96 TFA 102

¹H-NMR (CD₃OD/400 MHz): 7.45 (m, 1H), 7.32 (m, 4H), 5.05 (m, 2H), 3.80(m, 2H), 2.95 (m, 4H), 2.55 (m, 5H), 1.62 (m, 5H). 441.5      767/71 TFA103

¹H-NMR (CD₃OD/400 MHz): 7.34 (m, 2H), 7.14 (m, 2H), 6.80 (m, 1H), 4.94(m, 2H), 3.74 (m, 2H), 3.31 (m, 4H), 3.12 (m, 4H), 2.85 (m, 5H). 414.5    37000/42 2TFA 104

¹H-NMR (CD₃OD/400 MHz): 7.45 (m, 1H), 7.32 (m, 3H), 6.80 (m, 1H), 5.00(m, 2H), 3.76 (m, 4H), 3.38 (m, 4H), 2.96 (m, 2H), 2.88 (m, 5H). 430.3    17000/63 2TFA 105

¹H-NMR (CD₃OD/400 MHz): 7.46 (d, 2H), 7.36 (t, 1H), 7.05 (m, 1H), 5.22(m, 2H), 3.50 (m, 2H), 3.35 (m, 2H), 3.11 (m, 2H), 2.81 (m, 2H), 1.95(m, 2H), 1.45 (m, 4H), 1.30 (m, 6H). 477.4     3268/71 TFA 106

¹H-NMR (Acetone- d₆/400 MHz): 7.37 (m, 2H), 7.16 (m, 3H), 5.00 (m, 2H),3.90 (m, 2H), 3.60 (m, 6H), 3.25 (m, 6H), 1.34 (m, 3H). 428.5    6300/115 2TFA 107

¹H-NMR (CD₃OD/400 MHz): 7.45 (m, 1H), 7.34 (m, 3H), 6.80 (m, 1H), 5.01(m, 2H), 3.78 (m, 2H), 3.47 (m, 2H), 3.28 (m, 2H), 3.04 (m, 2H), 2.91(m, 4H). 465.4      873/85 TFA 108

¹H-NMR (CD₃OD/400 MHz): 7.40 (m, 2H), 7.20 (m, 3H), 5.00 (m, 2H), 3.65(m, 2H), 3.50 (m, 2H), 3.40 (m, 2H), 3.25 (m, 2H), 3.00 (m, 4H). 449.4    7800/92 TFA 109

¹H-NMR (CD₃OD/400 MHz): 7.40 (m, 1H), 7.10 (m, 3H), 5.05 (m, 2H), 3.65(m, 2H), 3.45 (m, 2H), 3.25 (m, 2H), 3.00 (m, 6H). 467.4     4200/94 TFA110

¹H-NMR (Acetone- d₆/400 MHz): 7.52 (m, 2H), 7.43 (m, 1H), 7.20 (m, 1H),5.20 (m, 2H), 3.60 (m, 2H), 3.00 (m, 10H). 499.3     1644/84 TFA 111

¹H-NMR (Acetone- d₆/400 MHz): 7.28 (m, 4H), 5.08 (m, 2H), 3.91 (m, 2H),3.60 (m, 2H), 3.16 (m, 8H). 467.4     13100/64 TFA 112

¹H-NMR (Acetone- d₆/400 MHz): 7.58 (m, 1H), 7.40 (m, 2H), 6.78 (m, 1H),5.04 (m, 2H), 3.90 (m, 2H), 3.71 (m, 2H), 3.47 (m, 4H), 3.14 (m, 4H).446.4     1066/91 2TFA 113

¹H-NMR (CD₃OD/400 MHz): δ 7.30 (m, 1H), 7.02 (m, 2H), 6.95 (m, 1H) 4.78(m, 2H), 3.57 (m, 2H), 2.65 (m, 1H), 2.02 (m, 2H), 1.78 (m, 4H). 418.0    77000/21 — 114

¹H-NMR (CD₃OD/400 MHz): δ 7.20 (m, 1H), 6.95 (m, 2H), 6.55 (m, 1H), 5.60(d, 2H), 4.70 (m, 2H), 3.57 (m, 2H), 2.60 (m, 1H), 2.02-1.80 (m, 6H).448.0 TBD — 115

¹H-NMR (CD₃OD/400 MHz): δ 7.34 (m, 1H), 7.05 (m, 2H), 6.55 (m, 1H), 4.95(d, 2H), 3.60 (m, 2H), 2.80 (m, 1H), 2.05 (m, 1H), 2.00 (m, 5H), 1.80(m, 5H), 1.00 (t, 3H). 437.1      98/104 TFA 116

¹H-NMR (CD₃OD/ 400 MHz): 8.50 (s, 1H), 8.38 (d, 1H), 7.43 (m, 1H), 6.55(m, 1H), 4.88 (m, 2H), 3.60 (m, 2H), 2.66 (m, 1H), 2.10- 1.20 (m, 6H).323.4     38000/NA TFA 117

¹H-NMR (CD₃OD/ 400 MHz): 8.44 (d, 1H), 8.15 (d, 1H), 7.43 (m, 1H), 6.60(m, 1H), 4.74 (m, 2H), 3.70 (m, 2H), 2.66 (m, 1H), 2.10- 1.20 (m, 6H).339.5 NA/NA TFA 118

¹H-NMR (CD₃OD/ 400 MHz): 11.4 (s, 1H), 7.57 (s, 1H), 7.43 (d, 1H), 7.21(t, 1H), 6.60-7.13 (m, 1H), 4.90 (m, 2H), 3.75 (m, 2H), 2.87 (s, 6H),2.71 (m, 1H), 2.10-1.50 (m, 6H). 400.4     7000/100 TFA 119

¹H-NMR (CD₃OD/ 400 MHz): 8.20 (m, 1H), 7.55 (m, 1H), 7.26 (m, 1H), 7.10(m, 1H), 6.32- 6.58 (m, 1H), 5.00 (s, 2H), 3.52 (m, 2H), 2.60 (m, 1H),2.00- 1.50 (m, 6H). 344.4     2933/100 — 120

¹H-NMR (CD₃OD/ 400 MHz): 8.20 (m, 1H), 7.56 (m, 1H), 7.28 (m, 1H), 7.11(m, 1H), 6.43- 6.67 (m, 1H), 5.05 (s, 2H), 3.54 (m, 2H), 2.61 (m, 1H),2.00- 1.50 (m, 6H). 388.4/ 390.4     1335/100 — 121

¹H-NMR (CD₃OD/ 400 MHz): 11.2 (s, 1H), 7.52 (nd, 1H), 7.41 (d, 1H), 7.21(t, 1H), 6.60-7.13 (m, 1H), 5.03 (bs, 2H), 3.80 (m, 2H), 2.73 (s, 6H),2.71 (m, 1H), 2.10-1.50 (m, 6H).    23,000/NA TFA 122

¹H-NMR (CD₃OD/ 400 MHz): 7.96 (m, 1H), 7.78 (m, 1H), 7.00 (m, 1H), 6.67-6.24 (m, 1H), 4.63 (m, 2H), 3.61 (m, 2H), 2.61 (m, 1H), 2.10-1.50 (m,6H). NA/NA — 123

¹H-NMR (CD₃OD/ 400 MHz): 8.20 (m, 1H), 7.57 (m, 1H), 7.29 (m, 1H), 7.14(m, 1H), 6.43- 6.67 (m, 1H), 5.03 (s, 2H), 3.54 (m, 2H), 2.61 (m, 1H),2.00- 1.50 (m, 6H).      828/100 — 124

¹H-NMR (CD₃OD/ 400 MHz): 7.08 (m, 1H), 7.00-6.60 (m, 3H), 4.80 (m, 2H),3.51 (m, 2H), 2.65 (m, 1H), 2.10-1.50 (m, 6H).      21/100 — 125

¹H-NMR (CD₃OD/ 400 MHz): 7.08 (m, 1H), 6.83 (m, 1H), 6.71 (m, 1H), 6.63-6.36 (m, 1H), 4.74 (m, 2H), 3.46 (m, 2H), 2.64 (m, 1H), 2.10- 1.50 (m,6H).      35/100 — 126

¹H-NMR (CD₃OD/ 400 MHz): 9.00- 8.40 (m, 1H), 7.75- 7.35 (m, 2H), 6.98(m, 1H), 5.18 (s, 2H), 3.56 (m, 2H), 2.65 (m, 1H), 2.10-1.50 (m, 6H).NA/NA — 127

¹H-NMR (CD₃OD/ 400 MHz): 7.44 (m, 1H), 7.32 (m, 4H), 4.86 (m, 2H), 3.58(m, 2H), 2.65 (m, 1H), 2.10-1.50 (m, 6H).      258/100 — 128

¹H-NMR (CD₃OD/ 400 MHz): 8.56 (s, 1H), 8.45 (m, 1H), 7.32 (m, 1H), 7.04(m, 1H), 4.88 (m, 2H), 3.70 (m, 2H), 2.68 (m, 1H), 2.10-1.50 (m, 6H).    9300/75 — 129

¹H-NMR (CD₃OD/ 400 MHz): rotomers 7.22 + 7.11 (t, 1H), 6.55 (m, 2H),6.31 + 6.27 (s, 1H), 4.98 + 4.70 (s, 2H), 3.98 + 3.58 (m, 2H), 2.59 +2.42 (m, 2H), 1.94 (m, 1H), 0.99 (m, 2H), 0.73 (m, 2H).     10500/NA —130

¹H-NMR (CD₃OD/ 400 MHz): 7.08 (m, 2H), 6.61 (d, 1H), 6.56 (dd, 1H), 4.80(m, 2H), 3.65 (m, 2H), 2.48 (m, 1H).     1000/100 — 131

¹H-NMR (CD₃OD/ 400 MHz): 7.14 (m, 2H), 6.60 (m, 1H), 6.54 (d, 1H), 4.73(m, 2H), 3.57 (m, 2H), 1.77 (m, 2H), 1.17 (s, 3H), 1.13 (s, 3H).    23000/NA — 132

¹H-NMR (CD₃OD/ 400 MHz): 7.07 (t, 1H), 6.59 (d, 1H), 6.52 (dd, 1H), 4.67(s, 2H), 4.54 (m, 1H), 2.00-1.50 (m, 8H).      213/100 — 133

¹H-NMR (CD₃OD/ 400 MHz): 7.08 (m, 1H), 6.84 (m, 1H), 6.63 (d, 1H), 6.58(dd, 1H), 4.82 (m, 2H), 3.73 (m, 2H), 3.11 (m, 2H).     1270/100 TFA 134

¹H-NMR (CD₃OD/ 400 MHz): 7.15- 6.55 (m, 4H), 4.73 (m, 2H), 3.51 (m, 2H),2.65 (m, 1H), 2.10- 1.50 (m, 6H).     1075/100 — 135

¹H-NMR (d₆DMSO/ 400 MHz): 11.2 (s, 1H), 7.33 (m, 3H), 7.06 (t, 1H), 6.88(d, 1H), 6.52 (m, 1H), 6.42 (s, 1H), 5.05 (s, 1H), 4.84 (d, 1H), 3.54(m, 1H), 1.94 (m, 2H), 1.68 (m, 2H), 1.53 (m, 2H).      68/100 TFA 136

¹H-NMR (CD₃OD/ 400 MHz): 7.10- 6.55 (m, 4H), 4.79 (s, 1H), 3.98 (s, 1H),3.59 (m, 1H), 2.65 (m, 2H), 2.10-1.50 (m, 6H).      380/100 — 137

¹H-NMR (CD₃OD/ 400 MHz): 7.30- 6.75 (m, 2H), 6.60 (d, 1H), 6.53 (d, 1H),4.77 (s, 2H), 3.74 (m, 2H), 3.59 (m, 2H).     6200/70 — 138

¹H-NMR (CD₃OD/ 400 MHz): 7.30- 6.75 (m, 2H), 6.60 (d, 1H), 6.53 (d, 1H),4.90 (m, 2H), 3.74 (m, 2H), 1.23 (m, 6H). NA/NA — 139

¹H-NMR (CD₃OD/ 400 MHz): 7.11 (m, 1H), 6.86 (m, 1H), 6.57 (d, 1H), 6.51(d, 1H), 4.70 (s, 2H), 4.10 (m, 1H), 1.77 (m, 5H), 1.58 (m, 4H),1.44-1.04 (m, 4H).      152/100 — 140

¹H-NMR (CD₃OD/ 400 MHz): rotomers 7.24 + 7.04 (t, 1H), 6.94 + 6.81 (s,1H), 6.60 (d, 1H), 6.53 (dd, 1H), 4.76 + 4.72 (s, 2H), 3.59 + 3.50 (m,2H), 1.48 (q, 2), 0.67 + 0.53 (m, 2H), 0.41 (m, 2H), 0.01 (m, 2H).     32/100 — 141

¹H-NMR (CD₃OD/ 400 MHz): 8.20- 6.60 (m, 4H), 4.81- 4.45 (m, 2H), 3.61(m, 1H), 3.22 (m, 1H), 2.65 (m, 1H), 2.10- 1.50 (m, 6H).     6500/100 —142

¹H-NMR (CD₃OD/ 400 MHz): 7.30- 6.75 (m, 2H), 6.59 (d, 1H), 6.53 (dd,1H), 4.76 (s, 2H), 3.63 (m, 4H), 3.31 (s, 3H).     1190/100 — 143

¹H-NMR (CD₃OD/ 400 MHz): 7.15 (nt, 1H), 6.97 (s, 1H), 6.65 (d, 1H), 6.59(dd, 1H), 4.91 (s, 2H), 3.80 (m, 2H), 3.25 (m, 6H), 1.30 (t, 6H).     108/100 TFA 144

¹H-NMR (CD₃OD/ 400 MHz): 9.38 (s, 1H), 7.78 (d, 1H), 7.67 (s, 1H), 7.60(t, 1H), 7.51 (m, 1H), 7.08 (s, 1H), 6.32 (s, 1H), 5.06 (s, 2H).    25000/NA TFA 145

¹H-NMR (CD₃OD/ 400 MHz): 7.50- 6.95 (m, 4H), 4.81 (s, 2H), 4.26 (s, 2H),3.82 (m, 2H), 2.72 (m, 1H), 2.10-1.50 (m, 6H).     25500/NA TFA 146

¹H-NMR (CD₃OD/ 400 MHz): 9.48 (m, 1H), 7.63 (t, 1H), 7.40-7.00 (m, 3H),6.62 (m, 1H), 4.49 (m, 2H), 4.26 (m, 2H). 385.5 NA/NA TFA 147

¹H-NMR (CD₃OD/ 400 MHz): 7.00 (m, 1H), 6.27 (m, 2H), 4.69 (s, 2H), 4.48(s, 2H), 3.56 (m, 2H), 2.68 (m, 1H), 2.10- 1.50 (m, 6H). 358.4 NA/NA —148

¹H-NMR (CD₃OD/ 400 MHz): 7.36 (m, 2H), 7.19 (m, 2H), 6.87 (s, 1H), 4.99(m, 2H), 3.86 (m, 2H), 3.30 (m, 6H), 1.31 (t, 6H). 387.5      505/100TFA 149

¹H-NMR (CD₃OD/ 400 MHz): 7.46- 7.06 (m, 4H), 7.00- 6.73 (m, 1H), 4.90(m, 2H), 3.65 (m, 2H), 1.51 (q, 2H), 0.62 (m, 1H), 0.42 (m, 2H), 0.02(m, 2H). 356.5     1995/100 — 150

¹H-NMR (CD₃OD/ 400 MHz): 7.46- 6.70 (m, 5H), 4.92 (m, 2H), 3.96-3.42 (m,6H), 2.68 (m, 1H), 2.02 (m, 1H), 1.62 (m, 1H). 372.4     16000/68 — 151

¹H-NMR (CD₃OD/ 400 MHz): 7.39- 7.09 (m, 5H), 4.87 (m, 2H), 4.00 (m, 1H),3.80 (m, 2H), 3.67 (m, 1H), 3.29 (m, 1H), 2.30 (m, 1H), 2.06 (m, 1H).358.4 NA/NA — 152

¹H-NMR (CD₃OD/ 400 MHz): 7.39 (m, 2H), 7.25 (t, 1H), 7.17 (t, 1H), 6.92(m, 1H), 5.02 (m, 2H), 4.34 (m, 1H), 3.96 (d, 1H), 3.86 (t, 1H),3.70-3.40 (m, 1H), 3.28 (m, 1H), 2.32 (m, 2H), 1.36 (t, 3H). 385.5    13500/68 TFA 153

¹H-NMR (CD₃OD/ 400 MHz): 7.32 (m, 2H), 7.10 (m, 2H), 6.98-6.51 (m, 1H),4.81 (s, 2H), 4.40- 4.00 (m, 1H), 1.79 (m, 4H), 1.70-1.04 (m, 6H). 370.5    19000/57 — 154

¹H-NMR (CD₃OD/ 400 MHz): 7.54- 6.72 (m, 5H), 5.04 (s, 2H), 3.86 (m, 2H),3.35 (m, 6H), 1.33 (t, 6H). 384.5     1430/100 TFA 155

¹H-NMR (CD₃OD/ 400 MHz): 7.35 (m, 2H), 7.19 (m, 2H), 6.81 (s, 1H), 5.03(s, 2H), 3.81 (m, 2H), 3.26 (m, 2H), 3.10 (q, 2H), 1.32 (t, 3H). 359.4    2150/100 TFA 156

¹H-NMR (CD₃OD/ 400 MHz): 7.66 (m, 1H), 7.53 (m, 1H), 7.27 (m, 2H), 6.93(s, 1H), 4.56 (s, 2H), 3.92 (m, 2H), 3.51 (m, 4H), 3.27 (m, 2H), 1.91(m, 2H), 1.65 (m, 2H), 1.05 (t, 3H), 0.89 (t, 3H). 415.5 NA/NA TFA 157

¹H-NMR (CD₃OD/ 400 MHz): 7.41 (m, 2H), 7.23 (m, 2H), 6.96 (s, 1H), 5.10(s, 2H), 3.78 (m, 4H), 3.24 (t, 2H), 1.34 (s, 12H). 415.5 NA/NA TFA 158

¹H-NMR (CD₃OD/ 400 MHz): 7.34 (m, 2H), 7.19 (m, 2H), 6.81 (s, 1H), 5.03(s, 2H), 4.20-3.40 (m, 6H), 3.15 (m, 2H), 2.10 (m, 4H). 385.4     265/100 TFA 159

¹H-NMR (CD₃OD/ 400 MHz): 7.49 (m, 1H), 7.39 (m, 3H), 6.72 (s, 1H), 5.07(s, 2H), 3.89 (m, 2H), 3.31 (m, 6H), 1.32 (t, 6H). 403.4      73/100 TFA160

¹H-NMR (CD₃OD/ 400 MHz): 9.24 (m, 1H), 7.80 (d, 1H), 7.61 (t, 1H), 7.47(m, 1H), 7.33-6.72 (m, 1H), 5.39 (m, 2H), 3.94 (m, 2H), 3.41 (m, 6H),1.33 (t, 6H). 409.5      825/100 TFA 161

¹H-NMR (CD₃OD/ 400 MHz): 7.45 (d, 1H), 7.33 (nd, 1H), 7.17 (t, 1H), 7.00(d, 1H), 6.94 (s, 1H), 6.37 (m, 1H), 5.24 (m, 2H), 3.88 (m, 2H),3.20-2.90 (m, 6H), 1.18 (t, 6H). 408.5      76/100 TFA 162

¹H-NMR (CD₃OD/ 400 MHz): 7.52- 7.22 (m, 5H), 5.03 (s, 2H), 3.85 (m, 4H),3.45 (m, 2H), 3.13 (m, 2H), 2.10 (m, 4H). 401.4      107/100 TFA 163

¹H-NMR (CD₃OD/ 400 MHz): 9.34 (s, 1H), 7.79 (d, 1H), 7.60 (t, 1H), 7.44(m, 1H), 7.33-6.72 (m, 1H), 5.38 (m, 2H), 4.30-3.40 (m, 6H), 3.17 (m,2H), 2.09 (m, 4H). 407.4     1085/100 TFA 164

¹H-NMR (CD₃OD/ 400 MHz): 7.41 (d, 1H), 7.31 (nd, 1H), 7.14 (t, 1H), 6.92(d, 1H), 6.78 (s, 1H), 6.39 (m, 1H), 5.20 (s, 2H), 3.86 (m, 2H), 3.70(m, 2H), 3.29 (m, 2H), 3.01 (m, 2H), 2.02 (m, 4H). 406.4      113/100TFA 165

¹H-NMR (CD₃OD/ 400 MHz): 7.55 (m, 1H), 7.37 (m, 1H), 7.29 (d, 1H), 5.02(s, 2H), 3.83 (m, 4H), 3.46 (m, 2H), 3.15 (m, 2H), 2.10 (m, 4H). 435.4 +437.4     45000/50 TFA 166

¹H-NMR (CD₃OD/ 400 MHz): 7.56 (s, 1H), 7.36 (m, 2H), 7.29-6.60 (m, 1H),5.04 (s, 2H), 3.84 (m, 2H), 3.32 (m, 6H), 1.32 (t, 6H). 437.4 + 439.4NA/NA TFA 167

¹H-NMR (CD₃OD/ 400 MHz): 7.65- 6.45 (m, 4H), 4.96 (m, 2H), 3.86 (m, 2H),3.30 (m, 6H), 1.32 (t, 6H). 437.4 + 439.4      186/100 TFA 168

¹H-NMR (CD₃OD/ 400 MHz): 7.55- 6.55 (m, 4H), 4.92 (m, 2H), 3.86 (m, 2H),3.30 (m, 6H), 1.32 (t, 6H). 437.4 + 439.4      97/100 TFA 169

¹H-NMR (CD₃OD/ 400 MHz): 7.51 (m, 2H), 7.41 (m, 1H), 7.20 (s, 1H), 5.32(s, 2H), 3.67 (m, 2H), 3.21 (m, 4H), 3.04 (m, 2H), 1.24 (t, 6H). 437.4 +439.4      66/100 TFA 170

¹H-NMR (CD₃OD/ 400 MHz): 7.36 (m, 2H), 7.21-6.68 (m, 2H), 5.03 (s, 2H),3.84 (m, 2H), 3.32 (m, 6H), 1.32 (t, 6H). 421.4      505/100 TFA 171

¹H-NMR (CD₃OD/ 400 MHz): 7.50 (m, 1H), 7.28-6.50 (m, 3H), 4.95 (m, 2H),3.87 (m, 2H), 3.30 (m, 6H), 1.33 (t, 6H). 421.4      88/100 TFA 172

¹H-NMR (CD₃OD/ 400 MHz): 7.43 (m, 1H), 7.35 (d, 1H), 7.20 (t, 1H), 7.16(s, 1H), 5.15 (s, 2H), 3.71 (m, 2H), 3.22 (m, 4H), 3.12 (m, 2H), 1.26(t, 6H). 421.4      94/100 TFA 173

¹H-NMR (CD₃OD/ 400 MHz): 7.52- 6.42 (m, 5H), 4.97 (s, 2H), 3.88 (m, 2H),3.68 (m, 2H), 3.32 (m, 2H), 2.97 (m, 2H), 1.96 (m, 2H), 1.78 (m, 3H),1.54 (m, 1H). 415.4      66/100 TFA 174

¹H-NMR (CD₃OD/ 400 MHz): 7.52- 6.42 (m, 5H), 5.03 (s, 2H), 4.20-3.45 (m,12H). 417.4     1495/100 TFA 175

¹H-NMR (CD₃OD/ 400 MHz): 7.45 (m, 1H), 7.34 (m, 3H), 6.87-6.44 (m, 1H),5.10 (s, 2H), 3.82 (m, 2H), 3.28 (m, 6H), 1.29 (t, 6H). 413.4 + 415.4     305/100 TFA 176

¹H-NMR (CD₃OD/ 400 MHz): 7.47 (m, 1H), 7.35 (m, 3H), 6.80-6.32 (m, 1H),5.06 (s, 2H), 3.83 (m, 2H), 3.29 (m, 6H), 1.30 (t, 6H). 369.4    1150/100 TFA 177

¹H-NMR (CD₃OD/ 400 MHz): 7.41 (m, 1H), 7.31 (m, 1H), 7.14 (m, 2H), 5.19(s, 2H), 3.71 (m, 4H), 3.33 (m, 2H), 3.08 (m, 2H), 2.08 (m, 4H). 419.4     180/100 TFA 178

¹H-NMR (CD₃OD/ 400 MHz): 7.48 (m, 2H), 7.38 (m, 1H), 7.18 (s, 1H), 5.31(s, 2H), 3.64 (m, 4H), 3.26 (m, 2H), 3.25 (m, 2H), 2.02 (m, 4H). 435.4     126/100 TFA 179

¹H-NMR (CD₃OD/ 400 MHz): 7.41 (m, 1H), 7.32 (m, 1H), 7.15 (m, 2H), 5.17(s, 2H), 3.73 (m, 2H), 3.56 (m, 2H), 3.18 (m, 2H), 2.93 (m, 2H), 1.92(m, 2H), 1.75 (m, 3H), 1.48 (m, 1H). 433.5      133/100 TFA 180

¹H-NMR (CD₃OD/ 400 MHz): 7.48 (m, 2H), 7.39 (m, 1H), 7.18 (s, 1H), 5.30(s, 2H), 3.68 (m, 2H), 3.52 (m, 2H), 3.10 (m, 2H), 2.90 (m, 2H), 1.90(m, 2H), 1.74 (m, 3H), 1.48 (m, 1H). 449.4      154/100 TFA 181

¹H-NMR (CD₃OD/ 400 MHz): 7.46 (m, 1H), 7.34 (m, 2H), 7.27 (m, 1H), 6.66(bs, 1H), 5.04 (s, 2H), 4.04 (m, 1H), 3.68 (m, 4H), 3.24 (m, 2H), 2.60(m, 2H), 1.39 (d, 3H). 415.5      430/100 TFA 182

¹H-NMR (CD₃OD/ 400 MHz): 7.39 (m, 1H), 7.26 (m, 1H), 7.17 (d, 1H), 6.66(bs, 1H), 5.08 (m, 2H), 3.86 (m, 2H), 3.30 (m, 6H), 1.32 (t, 6H). 421.5     109/100 TFA 183

¹H-NMR (CD₃OD/ 400 MHz): 7.34- 6.66 (m, 4H), 4.96 (s, 2H), 3.85 (m, 2H),3.29 (m, 6H), 1.31 (t, 6H). 418.5      185/100 TFA 184

¹H-NMR (CD₃OD/ 400 MHz): 7.41 (m, 1H), 7.37 (m, 1H), 7.24 (m, 1H), 7.16(m, 1H), 6.54 (bs, 1H), 5.01 (s, 2H), 3.89 (m, 2H), 3.31 (m, 6H), 2.99(m, 1H), 1.31 (t, 6H), 1.19 (d, 6H). 411.5     1950/85 TFA 185

¹H-NMR (CD₃OD/ 400 MHz): 7.45 (m, 1H), 7.33 (m, 3H), 7.15-6.59 (m, 1H),4.99 (s, 2H), 3.59 (m, 2H), 3.18 (m, 6H), 2.01 (m, 2H), 1.29 (t, 6H).417.4     1750/53 TFA 186

¹H-NMR (CD₃OD/ 400 MHz): 7.45 (m, 1H), 7.33 (m, 3H), 7.15-6.59 (m, 1H),4.97 (s, 2H), 3.61 (m, 2H), 3.16 (m, 6H), 2.88 (s, 6H), 2.00 (m, 2H).389.4      375/100 TFA 187

¹H-NMR (CD₃OD/ 400 MHz): 7.47 (m, 1H), 7.33 (m, 3H), 6.61 (bs, 1H), 5.04(bs, 2H), 3.87 (t, 2H), 3.38 (t, 6H), 2.97 (s, 6H). 375.4      295/100TFA 188

¹H-NMR (CD₃OD/ 400 MHz): 7.48 (m, 1H), 7.33 (m, 3H), 6.53 (bs, 1H), 4.99(bs, 2H), 3.90 (m, 2H), 3.59 (m, 2H), 3.35 (m, 2H), 2.52 (t, 2H), 1.88(m, 3H), 0.98 (m, 7H). 443.5      46/60 TFA 189

¹H-NMR (CD₃OD/ 400 MHz): 7.47 (m, 1H), 7.34 (m, 3H), 6.62 (bs, 1H), 5.03(bs, 2H), 3.88 (m, 2H), 3.56 (m, 2H), 3.37 (m, 2H), 3.25 (m, 2H), 1.93(m, 4H), 1.73 (m, 4H). 429.4      24/100 TFA 190

¹H-NMR (CD₃OD/ 400 MHz): 7.48 (m, 1H), 7.33 (m, 3H), 6.52 (bs, 1H), 4.98(bs, 2H), 3.88 (m, 2H), 3.71 (m, 2H), 3.33 (m, 2H), 2.97 (m, 2H), 1.93(m, 2H), 1.70 (m, 1H), 1.44 (m, 2H), 1.00 (d, 3H). 429.4      42/100 TFA191

¹H-NMR (CD₃OD/ 400 MHz): 7.48 (m, 1H), 7.33 (m, 3H), 6.50 (bs, 1H), 4.97(bs, 2H), 3.90 (m, 2H), 3.63 (m, 2H), 3.33 (m, 2H), 2.86 (t, 2H), 2.59(t, 2H), 1.86 (m, 4H), 1.18 (m, 1H), 1.00 (d, 3H). 429.4      29/100 TFA192

¹H-NMR (CD₃OD/ 400 MHz): 7.48 (m, 1H), 7.33 (m, 3H), 6.50 (bs, 1H), 4.99(bs, 2H), 3.90 (m, 2H), 3.62 (m, 2H), 3.33 (m, 2H), 2.05- 1.20 (m, 10H).429.4      104/100 TFA 193

¹H-NMR (CD₃OD/ 400 MHz): 7.40 (m, 4H), 4.94 (s, 2H), 3.76 (m, 2H), 3.22(m, 6H), 1.26 (t, 6H). 387.4     14000/58 TFA 194

¹H-NMR (CD₃OD/ 400 MHz): 7.18 (m, 1H), 6.92-6.66 (m, 3H), 4.87 (bs, 2H),3.81 (m, 2H), 3.50 (m, 2H), 3.28 (m, 4H), 1.93 (m, 4H), 1.73 (s, 4H).445.4      43/100 TFA 195

¹H-NMR (CD₃OD/ 400 MHz): 7.10 (m, 1H), 6.91 (bs, 1H), 6.62 (d, 1H), 6.57(d, 1H), 4.88 (bs, 2H), 3.80 (m, 2H), 3.51 (m, 2H), 3.26 (m, 4H), 1.91(m, 4H), 1.72 (s, 4H). 429.5      95/100 TFA 196

¹H-NMR (CD₃OD/ 400 MHz): 7.10 (m, 1H), 6.73 (m, 3H), 4.88 (bs, 2H), 3.86(m, 2H), 3.54 (m, 2H), 3.28 (m, 4H), 1.92 (m, 4H), 1.74 (s, 4H). 444.4     99/100 TFA 197

¹H-NMR (CD₃OD/ 400 MHz): 7.33 (m, 2H), 7.18 (m, 2H), 6.78 (bs, 1H), 5.00(bs, 2H), 3.85 (m, 2H), 3.55 (m, 2H), 3.37 (m, 2H), 3.25 (m, 2H), 1.91(m, 4H), 1.72 (s, 4H). 413.4      63/100 TFA 198

¹H-NMR (CD₃OD/ 400 MHz): 7.42 (m, 1H), 7.10- 6.95 (m, 32H), 5.09 (bs,2H), 3.79 (m, 2H), 3.51 (m, 2H), 3.31 (m, 2H), 3.21 (m, 2H), 1.90 (m,4H), 1.72 (s, 4H). 431.5      130/100 TFA 199

¹H-NMR (CD₃OD/ 400 MHz): 7.49 (m, 1H), 7.33 (m, 3H), (bs, 2H), 3.88 (m,2H), 3.70 (m, 2H), 3.33 (m, 2H), 2.97 (m, 2H), 2.00 (m, 2H), 1.38 (m,5H), 0.94 (t, 3H). 443.5      100/100 TFA 200

¹H-NMR (CD₃OD/ 400 MHz): 7.22 (m, 1H), 6.74 (m, 3H), 4.90 (bs, 2H), 3.88(m, 2H), 3.63 (m, 2H), 3.31 (m, 2H), 2.87 (t, 1H), 2.59 (t, 1H), 1.86(m, 4H), 1.18 (m, 1H), 1.00 (d, 3H). 444.5      130/100 TFA 201

¹H-NMR (CD₃OD/ 400 MHz): 7.34 (m, 2H), 7.18 (m, 2H), 6.81 (bs, 1H), 5.02(bs, 2H), 3.86 (m, 2H), 3.63 (m, 2H), 3.31 (m, 2H), 2.85 (t, 1H), 2.58(t, 1H), 1.85 (m, 4H), 1.16 (m, 1H), 0.98 (d, 3H). 413.5      215/100TFA 202

¹H-NMR (CD₃OD/ 400 MHz): 7.23 (m, 1H), 6.77 (m, 3H), 4.94 (bs, 2H), 3.86(m, 2H), 3.76 (m, 1H), 3.59 (m, 1H), 3.39 (m, 1H), 3.25 (m, 2H), 3.05(t, 1H), 2.06-1.68 (m, 5H), 1.57 (m, 2H), 1.38 (m, 3H). 444.4     395/100 TFA 203

¹H-NMR (CD₃OD/ 400 MHz): 7.36 (m, 2H), 7.18 (m, 2H), 6.85 (bs, 1H), 5.02(bs, 2H), 3.86 (m, 2H), 3.77 (m, 1H), 3.59 (m, 1H), 3.40 (m, 1H), 3.26(m, 2H), 2.85 (t, 1H), 2.58 (t, 1H), 2.22-1.68 (m, 5H), 1.58 (m, 2H),1.36 (m, 3H). 413.5      550/100 TFA 204

¹H-NMR (CD₃OD/ 400 MHz): 7.48 (m, 1H), 7.39 (m, 3H), 6.74 (bs, 1H), 5.07(m, 2H), 3.86 (m, 2H), 3.75 (m, 1H), 3.25 (m, 4H), 1.31 (m, 9H). 417.4     880/53 TFA 205

¹H-NMR (CD₃OD/ 400 MHz): 7.48 (m, 1H), 7.32 (m, 3H), 6.60 (bs, 1H), 5.04(s, 2H), 3.92 (m, 2H), 3.80-3.38 (m, 6H), 2.38 (m, 4H). 451.4    2050/100 TFA 206

¹H-NMR (CD₃OD/ 400 MHz): 7.32 (m, 1H), 7.15 (m, 2H), 6.92 (m, 1H), 6.75(bs, 1H), 5.27 (m, 2H), 3.88 (t, 2H), 3.73 (m, 2H), 3.33 (t, 2H), 3.04(m, 2H), 2.02 (m, 4H). 424.4      136/100 TFA 207

¹H-NMR (CD₃OD/ 400 MHz): 7.10 (d, 1H), 6.84 (m, 2H), 6.71 (d, 1H), 4.89(s, 2H), 3.80 (m, 2H), 3.49 (m, 2H), 3.22 (m, 4H), 1.90 (m, 4H), 1.72(s, 4H). 444.4      170/75 TFA 208

¹H-NMR (CD₃OD/ 400 MHz): 9.26 (m, 1H), 7.77 (m, 1H), 7.58 (m, 1H), 7.44(bs, 1H), 7.32-6.78, (m, 1H), 5.45-5.07 (m, 2H), 4.35-3.82 (m, 2H),3.78-3.20 (m, 6H), 1.92 (s, 4H), 1.73 (s, 4H). 435.5      125/100 TFA209

¹H-NMR (CD₃OD/ 400 MHz): 7.47 (m, 1H), 7.37 (m, 3H), 6.71 (s, 1H), 5.05(s, 2H), 3.86 (m, 2H), 3.50-3.20 (m, 4H), 3.13 (m, 2H), 1.71 (m, 2H),1.30 (t, 3H), 0.99 (t, 3H). 417.5      52/100 TFA 210

¹H-NMR (CD₃OD/ 400 MHz): 7.83 (m, 1H), 7.57 (m, 3H), 7.28-6.40, (m, 1H),5.45-4.90 (m, 2H), 3.90 (m, 2H), 3.60 (m, 2H), 3.46 (m, 2H), 3.28 (m,2H), 1.92 (m, 4H), 1.74 (s, 4H). 474.5      133/100 TFA 211

¹H-NMR (CD₃OD/ 400 MHz): 7.89 (m, 1H), 7.83 (m, 1H), 7.63 (m, 1H), 7.15(s, 1H), 5.24 (bs, 2H), 3.75 (m, 2H), 3.48 (m, 2H), 3.27 (m, 4H), 1.90(m, 4H), 1.73 (s, 4H). 474.5      123/100 TFA 212

¹H-NMR (CD₃OD/ 400 MHz): 7.49 (m, 1H), 7.39 (m, 3H), 6.76, (bs, 1H),5.04 (m, 2H), 3.75 (m, 2H), 3.58-3.10 (m, 4H), 2.01-1.25 (m, 12H). 443.5    5812/53 TFA 213

¹H-NMR (CD₃OD/ 400 MHz): 7.10 (t, 1H), 6.86 (d, 1H), 6.67 (bs, 1H), 6.60(d, 1H), 4.95 (s, 2H), 3.86 (t, 2H), 3.54 (m, 2H), 3.31 (t, 2H), 3.22(m, 2H), 1.92 (m, 4H), 1.73 (m, 4H). 444.4      60/100 TFA 214

¹H-NMR (CD₃OD/ 400 MHz): 7.40- 6.70 (m, 4H), 5.02 (m, 2H), 3.86 (m, 2H),3.57 (m, 2H), 3.40 (m, 2H), 3.28 (m, 2H), 1.92 (m, 4H), 1.73 (m, 4H).428.5      153/100 TFA 215

¹H-NMR (CD₃OD/ 400 MHz): 7.34 (m, 1H), 7.18 (m, 2H), 6.69 (bs, 1H), 4.95(bs, 2H), 3.86 (m, 5H), 3.56 (m, 2H), 3.38 (m, 2H), 3.28 (m, 2H), 1.92(m, 4H), 1.73 (bs, 4H). 440.5     1185/100 TFA 216

¹H-NMR (CD₃OD/ 400 MHz): 6.97 (t, 1H), 6.89 (m, 2H), 6.60 (m, 1H), 4.97(s, 2H), 3.84 (t, 2H), 3.52 (m, 2H), 3.31 (t, 2H), 3.22 (m, 2H), 1.90(m, 4H), 1.72 (m, 4H). 428.5      117/100 TFA 217

¹H-NMR (CD₃OD/ 400 MHz): 7.04 (t, 1H), 6.97 (d, 1H), 6.88 (bs, 1H), 6.78(d, 1H), 4.96 (s, 2H), 3.82 (t, 2H), 3.62 (s, 3H), 3.50 (m, 2H), 3.23(m, 4H), 1.90 (m, 4H), 1.72 (m, 4H). 440.5      230/100 TFA 218

¹H-NMR (CD₃OD/ 400 MHz): 7.52 (d, 1H), 7.19 (s, 1H), 7.09 (t, 1H), 6.76(d, 1H), 5.06 (bs, 2H), 4.41-3.29 (m, 6H), 3.06 (m, 2H), 1.87 (m, 4H),1.72 (m, 4H). 444.4      41/100 TFA 219

¹H-NMR (CD₃OD/ 400 MHz): 7.47 (m, 1H), 7.33 (m, 3H), 6.60 (bs, 1H), 5.03(bs, 2H), 4.12- 3.81 (m, 2H), 3.80- 3.48 (m, 2H), 3.36 (m, 2H), 3.06 (m,1H), 2.13 (m, 1H), 1.94 (m, 2H), 1.71 (m, 1H). 431.4     1300/100 TFA220

¹H-NMR (CD₃OD/ 400 MHz): 7.47 (m, 1H), 7.33 (m, 3H), 6.61 (bs, 1H), 5.02(bs, 2H), 4.21- 3.25 (m, 7H), 3.19- 2.62 (m, 2H), 2.35- 1.48 (m, 4H).431.4      465/100 TFA 221

¹H-NMR (CD₃OD/ 400 MHz): 7.43 (m, 1H), 7.36 (m, 2H), 7.13 (m, 1H), 5.08(q, 2H), 4.40-4.00 (m, 2H), 3.37 (m, 3H), 2.04 (m, 5H), 1.41 (d, 3H).430.4      223/60 TFA 222

¹H-NMR (CD₃OD/ 400 MHz): 7.50- 6.68 (m, 4H), 5.12 (s, 2H), 4.20 (t, 2H),3.81 (t, 2H), 3.43 (m, 4H), 2.10 (m, 4H). 416.5      56/100 TFA 223

¹H-NMR (CD₃OD/ 400 MHz): 7.46- 6.61 (m, 4H), 5.08 (m, 2H), 4.22-3.60 (m,2H), 3.14 (m, 2H), 2.98 (m, 2H), 1.75 (m, 1H), 1.58 (m, 2H), 1.34 (t,1H), 1.22 (t, 2H), 0.96 (m, 3H). 432.5      32/100 TFA 224

¹H-NMR (CD₃OD/ 400 MHz): rotomers 7.65-7.10 (m, 4H), 5.16 + 4.41 (s,2H), 3.92 + 3.31 (t, 2H), 3.16-3.01 (m, 5H), 2.96 (m, 4H), 2.88 (t, 1H).480.4      410/100 TFA 225

¹H-NMR (CD₃OD/ 400 MHz): 7.49 (m, 1H), 7.37 (m, 2H), 7.14 (m, 1H), 5.13(s, 2H), 4.22 (m, 2H), 4.06 (bs, 1H), 3.74 (t, 2H), 3.25 (m, 7H), 3.28(m, 4H), 2.14 (m, 1H), 1.77 (m, 3H). 446.4      102/100 TFA 226

¹H-NMR (CD₃OD/ 400 MHz): 7.50- 7.12 (m, 5H), 4.86 (m, 3H), 3.82 (m, 1H),2.81 (m, 2H), 2.39 (m, 2H). 356.3     12000/80 TFA 227

¹H-NMR (CD₃OD/ 400 MHz): 7.61- 7.22 (m, 4H), 6.54 (bs, 1H), 4.98 (m,1H), 4.61 (m, 1H), 4.45 (m, 1H), 4.32 (m, 1H), 4.00 (m, 1H), 3.83 (m,1H), 3.52 (m, 1H), 3.07 (m, 1H), 2.43 (m, 2H), 2.17 (m, 1H). 373.4     215/100 TFA 228

¹H-NMR (CD₃OD/ 400 MHz): 7.42 (m, 1H), 7.31 (m, 3H), 7.15 + 6.59 (bs,1H), 4.89 (m, 2H), 3.52 (m, 5H), 2.74 (m, 4H), 2.48 (m, 1H), 1.60 (m,6H), 1.07 (m, 1H). 493.4     2000/100 TFA 229

¹H-NMR (CD₃OD/ 400 MHz): 7.50- 6.90 (m, 9H), 6.72- 6.40 (m, 1H), 4.87(s, 1H), 4.70 (bs, 1H), 4.00-3.57 (m, 2H), 2.89 (m, 2H). 408.4 NA/NA —230

¹H-NMR (CD₃OD/ 400 MHz): 7.42 (m, 1H), 7.30 (m, 3H), 6.99 (d, 1H), 6.85(d, 1H), 6.78-6.42 (m, 3H), 4.86 (s, 1H), 4.74 (bs, 1H), 3.72 (m, 1H),3.58 (m, 1H), 2.78 (m, 2H). 424.4     12000/100 — 231

¹H-NMR (CD₃OD/ 400 MHz): 7.48 (m, 1H), 7.33 (m, 3H), 6.72 (bs, 1H), 5.09(m, 2H), 4.01 (m, 1H), 3.71 (m, 3H), 3.47 (m, 1H), 3.22 (m, 1H), 3.10(m, 1H), 2.24 (m, 1H), 2.07 (m, 2H), 1.88 (m, 1H), 1.36 (t, 1H). 415.5     148/65 TFA 232

¹H-NMR (CD₃OD/ 400 MHz): 7.56- 7.20 (m, 4H), , 6.49 (bs, 1H), 4.99 (bs,2H), 4.13 (m, 1H), 3.76 (m, 1H), 3.52 (m, 1H), 3.40 (m, 1H), 3.28 (m,1H), 2.05 (m, 3H), 1.73 (m, 1H). 387.5      320/85 TFA 233

¹H-NMR (CD₃OD/ 400 MHz): 7.53 (m, 2H), 7.44 (m, 1H), 7.37 (m, 1H), 4.88(m, 1H), 4.40 (s, 2H), 4.10 (m, 1H), 3.97 (m, 1H), 3.77 (m, 1H), 3.57(m, 1H), 2.66 (m, 1H), 2.52 (m, 1H). 388.4      930/75 TFA 234

¹H-NMR (CD₃OD/ 400 MHz): 7.60- 7.32 (m, 3H), 7.20- 6.66 (m, 1H), 5.13 +4.39 (s, 2H), 5.05 + 4.94 (bs, 1H), 4.56 (m, 1H), 4.21 + 3.87 (m, 1H),3.64 (m, 2H), 3.54 (m, 2H), 3.46 (m, 2H), 2.26 (m, 1H), 2.06 (m, 1H).432.5      111/100 TFA 235

¹H-NMR (CD₃OD/ 400 MHz): 7.60- 7.32 (m, 3H), 7.20- 6.66 (m, 1H), 5.12 +4.37 (s, 2H), 5.05 + 4.10 (bs, 1H), 4.18 (m, 1H), 4.20 + 3.84 (m, 1H),3.56 (m, 2H), 3.50 (m, 2H), 3.41 (m, 2H), 3.32 (d, 3H), 2.06 (m, 2H).446.5      133/100 TFA 236

¹H-NMR (CD₃OD/ 400 MHz): 7.60- 6.66 (m, 4H), 5.20- 4.45 (m, 3H), 5.05 +4.10 (bs, 1H), 4.00-4.12 (m, 1H), 3.80 + 3.52 (m, 2H), 3.41 (m, 2H),3.23- 2.78 (m, 3H), 2.06 (m, 2H), 1.82 (m, 2H). 448.4      160/73 TFA237

¹H-NMR (CD₃OD/ 400 MHz): 7.60- 6.66 (m, 4H), 5.12 + 4.38 (s, 2H), 5.00(m, 1H), 4.22 (m, 1H), 3.80-2.80 (m, 10H), 2.16-1.62 (m, 4H). 460.5     183/100 TFA 238

¹H-NMR (CD₃OD/ 400 MHz): 7.60- 6.66 (m, 4H), 5.14 + 4.38 (s, 2H), 5.07 +3.10 (bs, 1H), 4.24 + 3.92 (m, 1H), 3.82 (m, 4H), 3.51 (m, 3H), 3.41 (m,1H), 3.36 (m, 1H), 2.15 (m, 2H). 446.5      116/100 TFA 239

¹H-NMR (CD₃OD/ 400 MHz): 7.60- 6.66 (m, 4H), 5.13 + 4.39 (s, 2H), 4.99(m, 1H), 4.25 (m, 1H), 3.76 (m, 1H), 3.56 (m, 1H), 3.50- 3.00 (m, 6H),2.14 (m, 4H). 448.4      115/100 TFA 240

¹H-NMR (CD₃OD/ 400 MHz): 7.58- 6.35 (m, 4H), 5.08 (m, 2H), 4.22-3.60 (m,2H), 3.58-2.95 (m, 6H), 1.69 (m, 2H), 1.28 (m, 3H), 0.97 (m, 3H). 416.5     68/100 TFA 241

¹H-NMR (CD₃OD/ 400 MHz): 7.60- 6.62 (m, 4H), 5.55- 4.97 (m, 2H), 4.34(s, 1H), 4.19 + 3.80 (m, 1H), 3.76-3.05 (m, 7H), 2.30 (m, 2H). 434.4     125/100 TFA 242

¹H-NMR (CD₃OD/ 400 MHz): 7.60- 6.62 (m, 4H), 5.55- 4.97 (m, 2H), 4.34(s, 1H), 4.19 + 3.80 (m, 1H), 3.76-3.05 (m, 7H), 2.30 (m, 2H). 434.4     465/100 TFA 243

¹H-NMR (CD₃OD/ 400 MHz): 7.60- 6.60 (m, 4H), 5.16 + 4.24 (s, 2H), 4.95(m, 1H), 4.19 + 3.85 (m, 1H), 3.76-2.70 (m, 7H), 2.08 (m, 6H). 462.4     106/100 TFA 244

¹H-NMR (CD₃OD/400 MHz): 7.05 (m, 1H), 6.51 (m, 3H), 4.70 (m, 2H), 3.47(m, 2H), 2.64 (s, 1H), 2.00 (s, 2H), 1.80 (m, 4H). 337.9      62/107 —245

¹H-NMR (DMSO-d6/ 400 MHz): 13.84 (s, 1H), 9.87 (s, 1H), 7.05 (m, 1H),6.58 (m, 3H), 4.56 (m, 2H), 3.46 (m, 2H), 2.55 (m, 1H), 1.90- 1.54 (m,6H) 382.1      35/100 — 246

¹H-NMR (CDCl₃/400 MHz): 8.00 (s, 1H), 7.20 (m, 1H), 6.51 (m, 2H), 6.20(m, 1H), 4.70 (m, 2H), 3.50 (m, 2H), 2.64 (m, 1H), 1.99 (m, 2H),1.85-1.79 (m, 5H), 0.93 (m, 2H), 0.70 (m, 2H) 344.2      92/85 — *MaxResp. (%) represents the % maximum response in a biochemical assay ascompared with Fructose 1,6-bisphosphate. ^(†)Indicates salt form ifapplicable. TFA = trifluoroacetic acid

It is understood that any embodiment of the compounds of structure (I),including structures (Ia), (Ib) and (Ic), as set forth above, and any ofthe specific substituents set forth herein (e.g., R¹-R²³) in thecompounds of structures (I), (Ia), (Ib) and (Ic), as set forth above,may be independently combined with other embodiments and/or substituentsof compounds of structures (I), (Ia), (Ib) and (Ic) to form embodimentsof the inventions not specifically set forth above. In addition, in theevent that a list of substituents is listed for any particular R groupin a particular embodiment and/or claim, it is understood that eachindividual substituent may be deleted from the particular embodimentand/or claim and that the remaining list of substituents will beconsidered to be within the scope of the invention. It is understoodthat in the present description, combinations of substituents and/orvariables of the depicted formulae are permissible only if suchcontributions result in stable compounds.

The compounds of the present invention can be prepared according to anynumber of methods known in the art, including those methods specificallydescribed in the Examples below. The following General Reaction Scheme Iillustrates a method of making compounds of this invention, i.e.,compounds of structure (I), wherein R¹-R⁵ are as defined above.

Referring to General Reaction Scheme I, carbonyl compounds (e.g.,aldehydes or ketones) of structure A can be reacted under appropriatereductive amination conditions (e.g., MgSO₄/Na₂CO₃ in dichloromethanefollowed by NaBH₄) with amines (including salts thereof) of structure Bto yield amine C. Amine C is then reacted with acid D under appropriatecoupling conditions to yield E (a compound of structure (I) wherein R⁶is H). One of ordinary skill in the art will understand methods formaking compounds wherein R⁶ is other than H, for example by reaction ofthe imine obtained from reaction of A and B.

It is understood that one skilled in the art may be able to make thesecompounds by similar methods or by combining other methods known to oneskilled in the art. It is also understood that one skilled in the artwould be able to make, in a similar manner as described below, othercompounds of structure (I) not specifically illustrated below by usingthe appropriate starting components and modifying the parameters of thesynthesis as needed. In general, starting components may be obtainedfrom sources such as Sigma Aldrich, Lancaster Synthesis, Inc.,Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. orsynthesized according to sources known to those skilled in the art (see,for example, Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, 5th edition (Wiley, December 2000)) or prepared as describedin this invention.

It will also be appreciated by those skilled in the art that in theprocess described herein the functional groups of intermediate compoundsmay need to be protected by suitable protecting groups. Such functionalgroups include hydroxy, amino, mercapto and carboxylic acid. Suitableprotecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl(for example, t-butyldimethylsilyl, t-butyldiphenylsilyl ortrimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitableprotecting groups for amino, amidino and guanidino includet-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protectinggroups for mercapto include —C(O)—R¹¹ (where R¹¹ is alkyl, aryl orarylalkyl), p-methoxybenzyl, trityl and the like. Suitable protectinggroups for carboxylic acid include alkyl, aryl or arylalkyl esters.Protecting groups may be added or removed in accordance with standardtechniques, which are known to one skilled in the art and as describedherein. The use of protecting groups is described in detail in Green, T.W. and P. G. M. Wutz, Protective Groups in Organic Synthesis (1999), 3rdEd., Wiley. As one of skill in the art would appreciate, the protectinggroup may also be a polymer resin such as a Wang resin, Rink resin or a2-chlorotrityl-chloride resin.

It will also be appreciated by those skilled in the art, although suchprotected derivatives of compounds of this invention may not possesspharmacological activity as such, they may be administered to a mammaland thereafter metabolized in the body to form compounds of theinvention which are pharmacologically active. Such derivatives maytherefore be described as “prodrugs”. All prodrugs of compounds of thisinvention are included within the scope of the invention.

Furthermore, all compounds of the invention which exist in free base oracid form can be converted to their pharmaceutically acceptable salts bytreatment with the appropriate inorganic or organic base or acid bymethods known to one skilled in the art. Salts of the compounds of theinvention can be converted to their free base or acid form by standardtechniques.

II. Compositions and Administration

In other embodiments, the present invention is directed to apharmaceutical composition comprising any of the compounds describedherein, or a stereoisomer, pharmaceutically acceptable salt or prodrugthereof, and a pharmaceutically acceptable carrier, diluent orexcipient.

For the purposes of administration, the compounds of the presentinvention may be administered as a raw chemical or may be formulated aspharmaceutical compositions. Pharmaceutical compositions of the presentinvention comprise a compound of structure (I) (compounds of structure(I) include compounds of structures (Ia), (Ib) and (Ic)) and apharmaceutically acceptable carrier, diluent or excipient. The compoundof structure (I) is present in the composition in an amount which iseffective to treat a particular disease or condition of interest—thatis, in an amount sufficient to treat various cancers, and preferablywith acceptable toxicity to the patient. PKM2 activity of compounds ofstructure (I) can be determined by one skilled in the art, for example,as described in the Examples below. Appropriate concentrations anddosages can be readily determined by one skilled in the art.

Administration of the compounds of the invention, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration of agents for serving similar utilities. Thepharmaceutical compositions of the invention can be prepared bycombining a compound of the invention with an appropriatepharmaceutically acceptable carrier, diluent or excipient, and may beformulated into preparations in solid, semi-solid, liquid or gaseousforms, such as tablets, capsules, powders, granules, ointments,solutions, suppositories, injections, inhalants, gels, microspheres, andaerosols. Typical routes of administering such pharmaceuticalcompositions include, without limitation, oral, topical, transdermal,inhalation, parenteral, sublingual, buccal, rectal, vaginal, andintranasal. The term parenteral as used herein includes subcutaneousinjections, intravenous, intramuscular, intrasternal injection orinfusion techniques. Pharmaceutical compositions of the invention areformulated so as to allow the active ingredients contained therein to bebioavailable upon administration of the composition to a patient.Compositions that will be administered to a subject or patient take theform of one or more dosage units, where for example, a tablet may be asingle dosage unit, and a container of a compound of the invention inaerosol form may hold a plurality of dosage units. Actual methods ofpreparing such dosage forms are known, or will be apparent, to thoseskilled in this art; for example, see Remington: The Science andPractice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy andScience, 2000). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease or condition of interest in accordance with the teachingsof this invention.

A pharmaceutical composition of the invention may be in the form of asolid or liquid. In one aspect, the carrier(s) are particulate, so thatthe compositions are, for example, in tablet or powder form. Thecarrier(s) may be liquid, with the compositions being, for example, anoral syrup, injectable liquid or an aerosol, which is useful in, forexample, inhalatory administration.

When intended for oral administration, the pharmaceutical composition ispreferably in either solid or liquid form, where semi-solid,semi-liquid, suspension and gel forms are included within the formsconsidered herein as either solid or liquid.

As a solid composition for oral administration, the pharmaceuticalcomposition may be formulated into a powder, granule, compressed tablet,pill, capsule, chewing gum, wafer or the like form. Such a solidcomposition will typically contain one or more inert diluents or ediblecarriers. In addition, one or more of the following may be present:binders such as carboxymethylcellulose, ethyl cellulose,microcrystalline cellulose, gum tragacanth or gelatin; excipients suchas starch, lactose or dextrins, disintegrating agents such as alginicacid, sodium alginate, Primogel, corn starch and the like; lubricantssuch as magnesium stearate or Sterotex; glidants such as colloidalsilicon dioxide; sweetening agents such as sucrose or saccharin; aflavoring agent such as peppermint, methyl salicylate or orangeflavoring; and a coloring agent.

When the pharmaceutical composition is in the form of a capsule, forexample, a gelatin capsule, it may contain, in addition to materials ofthe above type, a liquid carrier such as polyethylene glycol or oil.

The pharmaceutical composition may be in the form of a liquid, forexample, an elixir, syrup, solution, emulsion or suspension. The liquidmay be for oral administration or for delivery by injection, as twoexamples. When intended for oral administration, preferred compositioncontain, in addition to the present compounds, one or more of asweetening agent, preservatives, dye/colorant and flavor enhancer. In acomposition intended to be administered by injection, one or more of asurfactant, preservative, wetting agent, dispersing agent, suspendingagent, buffer, stabilizer and isotonic agent may be included.

The liquid pharmaceutical compositions of the invention, whether they besolutions, suspensions or other like form, may include one or more ofthe following adjuvants: sterile diluents such as water for injection,saline solution, preferably physiological saline, Ringer's solution,isotonic sodium chloride, fixed oils such as synthetic mono ordiglycerides which may serve as the solvent or suspending medium,polyethylene glycols, glycerin, propylene glycol or other solvents;antibacterial agents such as benzyl alcohol or methyl paraben;antioxidants such as ascorbic acid or sodium bisulfite; chelating agentssuch as ethylenediaminetetraacetic acid; buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose. The parenteral preparation can be enclosedin ampoules, disposable syringes or multiple dose vials made of glass orplastic. Physiological saline is a preferred adjuvant. An injectablepharmaceutical composition is preferably sterile.

A liquid pharmaceutical composition of the invention intended for eitherparenteral or oral administration should contain an amount of a compoundof the invention such that a suitable dosage will be obtained.

The pharmaceutical composition of the invention may be intended fortopical administration, in which case the carrier may suitably comprisea solution, emulsion, ointment or gel base. The base, for example, maycomprise one or more of the following: petrolatum, lanolin, polyethyleneglycols, bee wax, mineral oil, diluents such as water and alcohol, andemulsifiers and stabilizers. Thickening agents may be present in apharmaceutical composition for topical administration. If intended fortransdermal administration, the composition may include a transdermalpatch or iontophoresis device.

The pharmaceutical composition of the invention may be intended forrectal administration, in the form, for example, of a suppository, whichwill melt in the rectum and release the drug. The composition for rectaladministration may contain an oleaginous base as a suitablenonirritating excipient. Such bases include, without limitation,lanolin, cocoa butter and polyethylene glycol.

The pharmaceutical composition of the invention may include variousmaterials, which modify the physical form of a solid or liquid dosageunit. For example, the composition may include materials that form acoating shell around the active ingredients. The materials that form thecoating shell are typically inert, and may be selected from, forexample, sugar, shellac, and other enteric coating agents.Alternatively, the active ingredients may be encased in a gelatincapsule.

The pharmaceutical composition of the invention in solid or liquid formmay include an agent that binds to the compound of the invention andthereby assists in the delivery of the compound. Suitable agents thatmay act in this capacity include a monoclonal or polyclonal antibody, aprotein or a liposome.

The pharmaceutical composition of the invention may consist of dosageunits that can be administered as an aerosol. The term aerosol is usedto denote a variety of systems ranging from those of colloidal nature tosystems consisting of pressurized packages. Delivery may be by aliquefied or compressed gas or by a suitable pump system that dispensesthe active ingredients. Aerosols of compounds of the invention may bedelivered in single phase, bi-phasic, or tri-phasic systems in order todeliver the active ingredient(s). Delivery of the aerosol includes thenecessary container, activators, valves, subcontainers, and the like,which together may form a kit. One skilled in the art, without undueexperimentation may determine preferred aerosols.

The pharmaceutical compositions of the invention may be prepared bymethodology well known in the pharmaceutical art. For example, apharmaceutical composition intended to be administered by injection canbe prepared by combining a compound of the invention with sterile,distilled water so as to form a solution. A surfactant may be added tofacilitate the formation of a homogeneous solution or suspension.Surfactants are compounds that non-covalently interact with the compoundof the invention so as to facilitate dissolution or homogeneoussuspension of the compound in the aqueous delivery system.

The compounds of the invention, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount, whichwill vary depending upon a variety of factors including the activity ofthe specific compound employed; the metabolic stability and length ofaction of the compound; the age, body weight, general health, sex, anddiet of the patient; the mode and time of administration; the rate ofexcretion; the drug combination; the severity of the particular disorderor condition; and the subject undergoing therapy.

Compounds of the invention, or pharmaceutically acceptable derivativesthereof, may also be administered simultaneously with, prior to, orafter administration of one or more other therapeutic agents. Suchcombination therapy includes administration of a single pharmaceuticaldosage formulation which contains a compound of the invention and one ormore additional active agents, as well as administration of the compoundof the invention and each active agent in its own separatepharmaceutical dosage formulation. For example, a compound of theinvention and the other active agent can be administered to the patienttogether in a single oral dosage composition such as a tablet orcapsule, or each agent administered in separate oral dosageformulations. Where separate dosage formulations are used, the compoundsof the invention and one or more additional active agents can beadministered at essentially the same time, i.e., concurrently, or atseparately staggered times, i.e., sequentially; combination therapy isunderstood to include all these regimens.

For any compound used in the methods of the invention, thetherapeutically effective amount or dose can be estimated initially fromcell culture assays. Then, the dosage can be formulated for use inanimal models so as to achieve a circulating concentration range thatincludes the IC50 as determined in cell culture (i.e., the concentrationof the test compound which achieves a half-maximal inhibition of theprotein kinase activity). Such information can then be used to moreaccurately determine useful doses in humans.

Toxicity and therapeutic efficacy of the compounds described herein canbe determined by standard pharmaceutical procedures in cell cultures orexperimental animals, e.g., by determining the IC50 and the LD50 (bothof which are discussed elsewhere herein) for a subject compound. Thedata obtained from these cell culture assays and animal studies can beused in formulating a range of dosage for use in humans. The dosage mayvary depending upon the dosage form employed and the route ofadministration utilized. The exact formulation, route of administrationand dosage can be chosen by the individual physician in view of thepatient's condition. (See, e.g., GOODMAN & GILMAN'S THE PHARMACOLOGICALBASIS OF THERAPEUTICS, Ch. 3, 9th ed., Ed. by Hardman, J., and Limbard,L., McGraw-Hill, New York City, 1996, p. 46.)

Dosage amount and interval may be adjusted individually to provideplasma levels of the active species which are sufficient to maintain thekinase modulating effects. These plasma levels are referred to asminimal effective concentrations (MECs). The MEC will vary for eachcompound but can be estimated from in vitro data, e.g., theconcentration necessary to achieve 50-90% inhibition of a kinase may beascertained using the assays described herein. Dosages necessary toachieve the MEC will depend on individual characteristics and route ofadministration. HPLC assays or bioassays can be used to determine plasmaconcentrations.

Dosage intervals can also be determined using MEC value. Compoundsshould be administered using a regimen that maintains plasma levelsabove the MEC for 10-90% of the time, preferably between 30-90% and mostpreferably between 50-90%.

At present, the therapeutically effective amounts of compounds of thepresent invention may range from approximately 2.5 mg/m2 to 1500 mg/m2per day. Additional illustrative amounts range from 0.2-1000 mg/qid,2-500 mg/qid, and 20-250 mg/qid.

In cases of local administration or selective uptake, the effectivelocal concentration of the drug may not be related to plasmaconcentration, and other procedures known in the art may be employed todetermine the correct dosage amount and interval.

The amount of a composition administered will, of course, be dependenton the subject being treated, the severity of the affliction, the mannerof administration, the judgment of the prescribing physician, etc.

The compositions may, if desired, be presented in a pack or dispenserdevice, such as an FDA approved kit, which may contain one or more unitdosage forms containing the active ingredient. The pack may for examplecomprise metal or plastic foil, such as a blister pack. The pack ordispenser device may be accompanied by instructions for administration.The pack or dispenser may also be accompanied by a notice associatedwith the container in a form prescribed by a governmental agencyregulating the manufacture, use or sale of pharmaceuticals, which noticeis reflective of approval by the agency of the form of the compositionsor of human or veterinary administration. Such notice, for example, maybe of the labeling approved by the U.S. Food and Drug Administration forprescription drugs or of an approved product insert. Compositionscomprising a compound of the invention formulated in a compatiblepharmaceutical carrier may also be prepared, placed in an appropriatecontainer, and labeled for treatment of an indicated condition. Suitableconditions indicated on the label may include treatment of a tumor,inhibition of angiogenesis, treatment of fibrosis, diabetes, and thelike.

III. Cancer Treatment Methods

In various other embodiments, the invention is directed to a method fortreating cancer by administering any of the above described compounds ofstructure (I) to a patient (e.g., mammal) in need thereof. In otherembodiments, the disclosure provides a method of activating PKM2 in amammal in need thereof, the method comprising administering to themammal an effective amount of any of the above described compounds ofstructure (I) or a pharmaceutical comprising the same. For example, theactivating of PKM2 may be for treatment of cancer, such as lung cancer.The invention also provides for treatment of various other cancers asdescribed below.

Representative compounds (Examples 1 and 244) of this inventiondemonstrate maximal activation levels similar to FBP (FIG. 1B and Table1, Example 245) and increased the affinity of PKM2 for PEP (FIG. 1C),but not ADP (FIG. 1D). A co-crystal structure of a representativecompound (Example 244) bound to tetrameric PKM2 at 2.03 Å resolution wasalso determined (FIG. 2, for simplicity, only the PKM2 dimer (half ofthe tetramer) crystal is shown, illustrating a novel 1:1 binding ratioof compound to monomer of PKM2; proposed hydrogen bonds are shown asdashed lines). While not wishing to be bound by theory, the resultsindicate that this compound did not bind to the FBP site, but insteadbound to an allosteric site of unknown physiological significance at thedimer-dimer interface. The compound appears to bind to the allostericsite with occupancy of two molecules per dimer (FIG. 2), whereas otherPKM2 activators (Boxer M B, Jiang J K, Vander Heiden M G, Shen M,Skoumbourdis A P, Southall N, et al. J Med Chem 2010; 53:1048-55; JiangJ K, Boxer M B, Vander Heiden M G, Shen M, Skoumbourdis A P, Southall N,et al. Bioorg Med Chem Lett 2010; 20:3387-93; Walsh M J, Brimacombe K R,Veith H, Bougie J M, Daniel T, Leister W, et al. Bioorg Med Chem Lett2011; 21:6322-7.) that bind to the same site did so with occupancy ofone molecule per dimer (PDB accession numbers: 3GQY, 3GR4, 3H6O, 3ME3).

Compounds of the invention were also determined to activate pyruvatekinase in cells. NCI-H1299 and A549 lung adenocarcinoma cell lines wereselected for this experiments due to previously reported high levels ofphospho-PKM2 at Tyr105 (Hitosugi T, Kang S, Vander Heiden M G, Chung TW, Elf S, Lythgoe K, et al. Sci Signal 2009; 2:ra73). Phosphorylation ofPKM2 at Tyr105 renders the enzyme insensitive to FBP activation.However, certain embodiments of the compounds described herein (e.g.,Examples 1 and 244) potently activate pyruvate kinase activity in bothcell lines (FIG. 3A and Table 2, Example 245). These resultsdemonstrated that the compounds effectively permeate the cell membraneto activate PKM2. In addition, these results demonstrated that highlevels of p-Tyr105 do not block activation by the PKM2 activators of theinvention, possibly due to the distinct allosteric binding mechanismdiscussed previously.

In certain embodiments, the compounds of the invention are also usefulto induce tetramer formation in cells. In this regard, FLAG-PKM2expressing HEK-293 cells were treated with compounds of the invention,and FLAG-PKM2 proteins were immunoprecipitated as previously described(Anastasiou D, Poulogiannis G, Asara J M, Boxer M B, Jiang J K, Shen M,et al. Science 2011; 334:1278-83). As shown in FIG. 3B, representativecompounds increased the amount of endogenous PKM2 thatco-immunoprecipitated with FLAG-PKM2, consistent with an increase ofFLAG-tagged and endogenous PKM2 tetramer complexes. Tetramers induced byrepresentative compounds in cells are relatively stable as demonstratedby the slow kinetics of PKM2 inactivation following compound washout(FIG. 3C).

In other embodiments, the compounds of the present invention inhibitcancer cell proliferation. Under normal media conditions, PKM2activators had no observable growth effect against a broad panel ofadherent and suspension cancer cell lines. However, when A549 cells weregrown in BME media lacking nonessential amino acids, representativecompounds inhibited proliferation with EC50 values of 210 nM and 89 nMrespectively (FIG. 4A). The inhibition of cell growth was rescued byadding serine (30 μM) to the media (FIG. 4B), suggesting that serinedeprivation sensitizes A459 cells to PKM2 activation.

The effect of a representative compound (Example 1) on 6 different celllines was also determined (FIG. 4C). These cell lines grew slowly orwell in media lacking serine, with moderate or no additional growthbenefit when serine was added to the media (data not shown). While notwishing to be bound by theory, it is believed that these cell lines haverobust de novo serine biosynthesis. As seen in FIG. 4C, the compound ofExample 1 was able to inhibit cell proliferation of certain cell linesat IC50 values as low as 0.1 μM. Cell lines from additional indicationsother than lung cancer (breast, colon, pancreas, prostate) were alsoexamined and found to have varying sensitivities to both serinedeprivation and treatment with a representative compound (data notshown). While not wishing to be bound by theory, it is possible thatcell line sensitivity to PKM2 activators in the absence of serine mightcorrelate with PKM2 phosphorylation at Tyr105, either in normal orserine-free media.

Compounds of the present invention also demonstrate efficacy in asubcutaneous A549 xenograft tumor model. A daily dose of 50 mg/kg ofrepresentative compounds administered intraperitoneally significantlyslowed tumor growth in two separate xenograft experiments (FIGS. 5A and5B). The slowed xenograft tumor growth compares with reports in PKM2genetic models, where PKM2 was replaced with constitutively active PKM1(Christofk H R, Vander Heiden M G, Harris M H, Ramanathan A, Gerszten RE, Wei R, et al. Nature 2008; 452:230-3), or where PKM2 was compared toa mutant resistant to inactivation due to phosphorylation at Tyr105(Hitosugi T, Kang S, Vander Heiden M G, Chung T W, Elf S, Lythgoe K, etal. Sci Signal 2009; 2:ra73). The present inventors believe theseexperiments are the first documented evidence that pharmacologicalactivation of PKM2 slows tumor growth in vivo. Importantly, nosignificant body weight loss or other gross toxicity was observed in thecohorts receiving the representative compounds (data not shown),suggesting few on- or off-target toxic effects.

While not wishing to be bound by theory, the above results indicate thatcertain embodiments of the present compounds are useful for treatingcancers where de novo serine biosynthesis is required for tumor growthand regulated by PKM2 inactivation. The serine-rescue experiments withA549 and other lung cancer cell lines suggest that synthesis of serineis necessary for these cells to proliferate, and that pharmacologicalPKM2 activation leads to increased glycolytic flux that deprives theserine biosynthetic pathway of starting material.

As mentioned above, the compounds and compositions of the invention willfind utility in a broad range of diseases and conditions mediated byPKM2. Such diseases may include by way of example and not limitation,cancers such as lung cancer, NSCLC (non-small cell lung cancer),oat-cell cancer, bone cancer, pancreatic cancer, skin cancer,dermatofibrosarcoma protuberans, cancer of the head and neck, cutaneousor intraocular melanoma, uterine cancer, ovarian cancer, colo-rectalcancer, cancer of the anal region, stomach cancer, colon cancer, breastcancer, gynecologic tumors (e.g., uterine sarcomas, carcinoma of thefallopian tubes, carcinoma of the endometrium, carcinoma of the cervix,carcinoma of the vagina or carcinoma of the vulva), Hodgkin's Disease,hepatocellular cancer, cancer of the esophagus, cancer of the smallintestine, cancer of the endocrine system (e.g., cancer of the thyroid,pancreas, parathyroid or adrenal glands), sarcomas of soft tissues,cancer of the urethra, cancer of the penis, prostate cancer(particularly hormone-refractory), chronic or acute leukemia, solidtumors of childhood, hypereosinophilia, lymphocytic lymphomas, cancer ofthe bladder, cancer of the kidney or ureter (e.g., renal cell carcinoma,carcinoma of the renal pelvis), pediatric malignancy, neoplasms of thecentral nervous system (e.g., primary CNS lymphoma, spinal axis tumors,medulloblastoma, brain stem gliomas or pituitary adenomas), Barrett'sesophagus (pre-malignant syndrome), neoplastic cutaneous disease,psoriasis, mycoses fungoides, and benign prostatic hypertrophy, diabetesrelated diseases such as diabetic retinopathy, retinal ischemia, andretinal neovascularization, hepatic cirrhosis, angiogenesis,cardiovascular disease such as atherosclerosis, immunological diseasesuch as autoimmune disease and renal disease.

In some embodiments, the compounds and compositions of the invention canbe used in methods for treating cancers such as hematologicalmalignancies. For example, in some embodiments the compounds andcompositions of the invention can be used in methods for treating acutemyeloid leukemia (AML). Other methods include treatment of bladdercancer, or treatment of prostate cancer.

The inventive compounds (i.e., compounds of structure (I)) can be usedin combination with one or more other chemotherapeutic agents. Thedosage of the inventive compounds may be adjusted for any drug-drugreaction. In one embodiment, the chemotherapeutic agent is selected fromthe group consisting of mitotic inhibitors, alkylating agents,anti-metabolites, cell cycle inhibitors, enzymes, topoisomeraseinhibitors such as CAMPTOSAR (irinotecan), biological responsemodifiers, anti-hormones, antiangiogenic agents such as MMP-2, MMP-9 andCOX-2 inhibitors, anti-androgens, platinum coordination complexes(cisplatin, etc.), substituted ureas such as hydroxyurea;methylhydrazine derivatives, e.g., procarbazine; adrenocorticalsuppressants, e.g., mitotane, aminoglutethimide, hormone and hormoneantagonists such as the adrenocorticosteriods (e.g., prednisone),progestins (e.g., hydroxyprogesterone caproate), estrogens (e.g.,diethylstilbesterol), antiestrogens such as tamoxifen, androgens, e.g.,testosterone propionate, and aromatase inhibitors, such as anastrozole,and AROMASIN (exemestane).

Examples of alkylating agents that the above method can be carried outin combination with include, without limitation, fluorouracil (5-FU)alone or in further combination with leukovorin; other pyrimidineanalogs such as UFT, capecitabine, gemcitabine and cytarabine, the alkylsulfonates, e.g., busulfan (used in the treatment of chronicgranulocytic leukemia), improsulfan and piposulfan; aziridines, e.g.,benzodepa, carboquone, meturedepa and uredepa; ethyleneimines andmethylmelamines, e.g., altretamine, triethylenemelamine,triethylenephosphoramide, triethylenethiophosphoramide andtrimethylolmelamine; and the nitrogen mustards, e.g., chlorambucil (usedin the treatment of chronic lymphocytic leukemia, primarymacroglobulinemia and non-Hodgkin's lymphoma), cyclophosphamide (used inthe treatment of Hodgkin's disease, multiple myeloma, neuroblastoma,breast cancer, ovarian cancer, lung cancer, Wilm's tumor andrhabdomyosarcoma), estramustine, ifosfamide, novembrichin, prednimustineand uracil mustard (used in the treatment of primary thrombocytosis,non-Hodgkin's lymphoma, Hodgkin's disease and ovarian cancer); andtriazines, e.g., dacarbazine (used in the treatment of soft tissuesarcoma).

Examples of antimetabolite chemotherapeutic agents that the above methodcan be carried out in combination with include, without limitation,folic acid analogs, e.g., methotrexate (used in the treatment of acutelymphocytic leukemia, choriocarcinoma, mycosis fungiodes, breast cancer,head and neck cancer and osteogenic sarcoma) and pteropterin; and thepurine analogs such as mercaptopurine and thioguanine which find use inthe treatment of acute granulocytic, acute lymphocytic and chronicgranulocytic leukemias.

Examples of natural product-based chemotherapeutic agents that the abovemethod can be carried out in combination with include, withoutlimitation, the vinca alkaloids, e.g., vinblastine (used in thetreatment of breast and testicular cancer), vincristine and vindesine;the epipodophyllotoxins, e.g., etoposide and teniposide, both of whichare useful in the treatment of testicular cancer and Kaposi's sarcoma;the antibiotic chemotherapeutic agents, e.g., daunorubicin, doxorubicin,epirubicin, mitomycin (used to treat stomach, cervix, colon, breast,bladder and pancreatic cancer), dactinomycin, temozolomide, plicamycin,bleomycin (used in the treatment of skin, esophagus and genitourinarytract cancer); and the enzymatic chemotherapeutic agents such asL-asparaginase.

Examples of useful COX-II inhibitors include Vioxx, CELEBREX(celecoxib), valdecoxib, paracoxib, rofecoxib, and Cox 189.

Examples of useful matrix metalloproteinase inhibitors are described inWO 96/33172 (published Oct. 24, 1996), WO 96/27583 (published Mar. 7,1996), European Patent Application No. 97304971.1 (filed Jul. 8, 1997),European Patent Application No. 99308617.2 (filed Oct. 29, 1999), WO98/07697 (published Feb. 26, 1998), WO 98/03516 (published Jan. 29,1998), WO 98/34918 (published Aug. 13, 1998), WO 98/34915 (publishedAug. 13, 1998), WO 98/33768 (published Aug. 6, 1998), WO 98/30566(published Jul. 16, 1998), European Patent Publication 606,046(published Jul. 13, 1994), European Patent Publication 931,788(published Jul. 28, 1999), WO 90/05719 (published May 31, 1990), WO99/52910 (published Oct. 21, 1999), WO 99/52889 (published Oct. 21,1999), WO 99/29667 (published Jun. 17, 1999), PCT InternationalApplication No. PCT/IB98/01113 (filed Jul. 21, 1998), European PatentApplication No. 99302232.1 (filed Mar. 25, 1999), Great Britain patentapplication number 9912961.1 (filed Jun. 3, 1999), U.S. Pat. No.5,863,949 (issued Jan. 26, 1999), U.S. Pat. No. 5,861,510 (issued Jan.19, 1999), and European Patent Publication 780,386 (published Jun. 25,1997), all of which are incorporated herein in their entireties byreference. Preferred MMP-2 and MMP-9 inhibitors are those that havelittle or no activity inhibiting MMP-1. More preferred are those thatselectively inhibit MMP-2 and/or MMP-9 relative to the othermatrix-metalloproteinases (i.e., MMP-1, MMP-3, MMP-4, MMP-5, MMP-6,MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).

Some specific examples of MMP inhibitors useful in the present inventionare AG-3340, RO 32-3555, RS 13-0830, and compounds selected from:3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl)-amino]-propionicacid;3-exo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylicacid hydroxyamide; (2R,3R)1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylicacid hydroxyamide;4-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylicacid hydroxyamide;3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl)-amino]-propionicacid;4-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylicacid hydroxyamide; (R)3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxylicacid hydroxyamide; (2R,3R)1-[4-(4-fluoro-2-methylbenzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylicacid hydroxyamide;3-[[(4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-1-methyl-ethyl)-amino]-propionicacid;3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(4-hydroxycarbamoyl-tetrahydro-pyran-4-yl)-amino]-propionicacid;3-exo-3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylicacid hydroxyamide;3-endo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylicacid hydroxyamide; and (R)3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylicacid hydroxyamide; and pharmaceutically acceptable salts and solvates ofthese compounds.

Other anti-angiogenesis agents, other COX-II inhibitors and other MMPinhibitors, can also be used in the present invention.

An inventive compound can also be used with signal transductioninhibitors, such as agents that can inhibit EGFR (epidermal growthfactor receptor) responses, such as EGFR antibodies, EGF antibodies, andmolecules that are EGFR inhibitors; VEGF (vascular endothelial growthfactor) inhibitors; and erbB2 receptor inhibitors, such as organicmolecules or antibodies that bind to the erbB2 receptor, such asHERCEPTIN (Genentech, Inc., South San Francisco, Calif.). EGFRinhibitors are described in, for example in WO 95/19970 (published Jul.27, 1995), WO 98/14451 (published Apr. 9, 1998), WO 98/02434 (publishedJan. 22, 1998), and U.S. Pat. No. 5,747,498 (issued May 5, 1998), andsuch substances can be used in the present invention as describedherein.

EGFR-inhibiting agents include, but are not limited to, the monoclonalantibodies C225 and anti-EGFR 22Mab (ImClone Systems, Inc., New York,N.Y.), the compounds ZD-1839 (AstraZeneca), BIBX-1382 (BoehringerIngelheim), MDX-447 (Medarex Inc., Annandale, N.J.), and OLX-103 (Merck& Co., Whitehouse Station, N.J.), and EGF fusion toxin (Seragen Inc.,Hopkinton, Mass.).

These and other EGFR-inhibiting agents can be used in the presentinvention. VEGF inhibitors, for example SU-5416 and SU-6668 (Sugen Inc.,South San Francisco, Calif.), can also be combined with an inventivecompound. VEGF inhibitors are described in, for example, WO 01/60814 A3(published Aug. 23, 2001), WO 99/24440 (published May 20, 1999), PCTInternational Application PCT/IB99/00797 (filed May 3, 1999), WO95/21613 (published Aug. 17, 1995), WO 99/61422 (published Dec. 2,1999), U.S. Pat. No. 5,834,504 (issued Nov. 10, 1998), WO 01/60814, WO98/50356 (published Nov. 12, 1998), U.S. Pat. No. 5,883,113 (issued Mar.16, 1999), U.S. Pat. No. 5,886,020 (issued Mar. 23, 1999), U.S. Pat. No.5,792,783 (issued Aug. 11, 1998), WO 99/10349 (published Mar. 4, 1999),WO 97/32856 (published Sep. 12, 1997), WO 97/22596 (published Jun. 26,1997), WO 98/54093 (published Dec. 3, 1998), WO 98/02438 (published Jan.22, 1998), WO 99/16755 (published Apr. 8, 1999), and WO 98/02437(published Jan. 22, 1998), all of which are incorporated herein in theirentireties by reference. Other examples of some specific VEGF inhibitorsuseful in the present invention are IM862 (Cytran Inc., Kirkland,Wash.); anti-VEGF monoclonal antibody of Genentech, Inc.; and angiozyme,a synthetic ribozyme from Ribozyme (Boulder, Colo.) and Chiron(Emeryville, Calif.). These and other VEGF inhibitors can be used in thepresent invention as described herein. pErbB2 receptor inhibitors, suchas GW-282974 (Glaxo Wellcome plc), and the monoclonal antibodies AR-209(Aronex Pharmaceuticals Inc., The Woodlands, Tex.) and 2B-1 (Chiron),can furthermore be combined with an inventive compound, for example,those indicated in WO 98/02434 (published Jan. 22, 1998), WO 99/35146(published Jul. 15, 1999), WO 99/35132 (published Jul. 15, 1999), WO98/02437 (published Jan. 22, 1998), WO 97/13760 (published Apr. 17,1997), WO 95/19970 (published Jul. 27, 1995), U.S. Pat. No. 5,587,458(issued Dec. 24, 1996), and U.S. Pat. No. 5,877,305 (issued Mar. 2,1999), which are all hereby incorporated herein in their entireties byreference. ErbB2 receptor inhibitors useful in the present invention arealso described in U.S. Pat. No. 6,284,764 (issued Sep. 4, 2001),incorporated in its entirety herein by reference. The erbB2 receptorinhibitor compounds and substance described in the aforementioned PCTapplications, U.S. patents, and U.S. provisional applications, as wellas other compounds and substances that inhibit the erbB2 receptor, canbe used with an inventive compound, in accordance with the presentinvention.

An inventive compound can also be used with other agents useful intreating cancer, including, but not limited to, agents capable ofenhancing antitumor immune responses, such as CTLA4 (cytotoxiclymphocyte antigen 4) antibodies, and other agents capable of blockingCTLA4; and anti-proliferative agents such as other farnesyl proteintransferase inhibitors, for example the farnesyl protein transferaseinhibitors described in the references cited in the “Background”section, of U.S. Pat. No. 6,258,824 B1.

The above method can also be carried out in combination with radiationtherapy, wherein the amount of an inventive compound in combination withthe radiation therapy is effective in treating the above diseases.

Techniques for administering radiation therapy are known in the art, andthese techniques can be used in the combination therapy describedherein. The administration of the compound of the invention in thiscombination therapy can be determined as described herein.

The following examples are provided for purposes of illustration, notlimitation.

EXAMPLES Example 1 Synthesis ofN-(cyclobutylmethyl)-N-(2-fluoro-4-hydroxybenzyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

To a solution of 2-fluoro-4-hydroxybenzaldehyde (0.5 g, 3.57 mmol) andcyclobutylmethanamine hydrogen chloride (0.304 g, 3.57 mmol) inmethylene chloride (5 mL) was added MgSO₄ (1.29 g, 10.71 mmol) andNa₂CO₃ (0.78 g, 7.14 mmol). The mixture was stirred at room temperatureovernight, and then NaBH₄ (0.16 g, 3.57 mmol) was added and stirredadditional 16 h. It was quenched with methanol and diluted with 20 mLmethylene chloride, and washed with water 10 mL. The aqueous layer wasextracted with three 15 mL portions of methylene chloride. The combinedorganic extracts were washed with 10 mL of brine, dried with Na₂SO₄ andconcentrated. The residue was purified by chromatography on silica geleluting with 0 to 10% methanol in methylene chloride to give (0.7 g,3.35 mmol, 94% yield) of compound4-(((cyclobutylmethyl)amino)methyl)-3-fluorophenol.

To a solution of 3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (0.1g, 0.555 mmol) and 4-(((cyclobutylmethyl)amino)methyl)-3-fluorophenol(0.116 g, 0.555 mmol) in DMF (1 mL) was added EDCI (0.160 g, 0.833mmol), HOAt (0.133 g, 0.833 mmol) and 4-methylmorpholine (0.168 g, 1.666mmol). Then the reaction mixture was stirred at r.t. overnight. Theresulting reaction mixture was diluted with 30 mL DCM and washed withwater 20 mL. The aqueous layer was extracted with three 15 mL portionsof methylene chloride. The combined organic extracts were washed with 10mL of brine, dried with Na₂SO₄ and concentrated. The residue waspurified by chromatography on silica gel eluting with 0 to 15% methanolin methylene chloride to give (0.050 g, 0.135 mmol, 24% yield) ofcompoundN-(cyclobutylmethyl)-N-(2-fluoro-4-hydroxybenzyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

¹H-NMR (CDCl₃/400 MHz): 7.10 (m, 1H), 6.80 (m, 1H), 6.59 (d, J=8.4 Hz,1H), 6.52 (d, J=12.0 Hz, 1H), 4.69 (s, 2H), 3.50 (s, 2H), 2.65 (m, 1H),2.00-1.58 (m, 6H). MS (ES⁺, m/z): 372.1 (M⁺+1, 100.0).

Example 2 Synthesis of3-cyano-N-(cyclobutylmethyl)-N-(2-fluoro-4-hydroxybenzyl)-1H-pyrazole-5-carboxamide

To a solution of 3-cyano-1H-pyrazole-5-carboxylic acid (0.100 g, 0.729mmol) and 4-(((cyclobutylmethyl)amino)methyl)-3-fluorophenol (0.153 g,0.729 mmol) in DMF (1 mL) was added EDCI (0.210 g, 1.094 mmol), HOBt(0.148 g, 1.094 mmol) and DIPEA (0.283 g, 2.188 mmol). Then the reactionmixture was stirred at r.t. overnight. The resulting reaction mixturewas diluted with 30 mL DCM and washed with water 20 mL. The aqueouslayer was extracted with three 15 mL portions of methylene chloride. Thecombined organic extracts were washed with 10 mL of brine, dried withNa₂SO₄ and concentrated. The residue was purified by chromatography onsilica gel eluting with 0 to 15% methanol in methylene chloride to give(0.026 g, 0.079 mmol, 11% yield) of compound3-cyano-N-(cyclobutylmethyl)-N-(2-fluoro-4-hydroxybenzyl)-1H-pyrazole-5-carboxamide.

¹H-NMR (CD₃OD/400 MHz): 7.05 (m, 2H), 6.54 (m, 2H), 4.68 (m, 2H), 3.67(m, 1H), 3.46 (m, 1H), 2.67 (m, 1H), 2.01-1.62 (m, 6H). MS (ES⁺, m/z):328.9 (M⁺+1, 100.0).

Compounds in Examples 2-28, 245 and 246 were prepared using a methodanalagous to that described in Example 1.

Example 3 Synthesis of3-amino-N-(cyclobutylmethyl)-N-(2-fluoro-4-hydroxybenzyl)-1H-pyrazole-5-carboxamide

To a solution of 3-amino-1H-pyrazole-5-carboxylic acid (0.100 g, 0.787mmol) and 4-(((cyclobutylmethyl)amino)methyl)-3-fluorophenol (0.165 g,0.787 mmol) in DMF (1 mL) was added EDCI (0.226 g, 1.180 mmol), HOAt(0.159 g, 1.18 mmol) and 4-methylmorpholine (0.040 g, 0.126 mmol). Thenthe reaction mixture was stirred at r.t. overnight. The resultingreaction mixture was diluted with 30 mL DCM and washed with water 20 mL.The aqueous layer was extracted with three 15 mL portions of methylenechloride. The combined organic extracts were washed with 10 mL of brine,dried with Na₂SO₄ and concentrated. The residue was chromatographyeluting with 0 to 15% methanol in methylene chloride to give (0.040 g,0.126 mmol, 16% yield) of compound3-amino-N-(cyclobutylmethyl)-N-(2-fluoro-4-hydroxybenzyl)-1H-pyrazole-5-carboxamide.

¹H-NMR (CD₃OD/400 MHz): 7.08 (m, 1H), 6.54 (m, 2H), 5.70 (m, 1H), 4.63(m, 2H), 3.64 (m, 1H), 3.56 (m, 1H), 2.64 (m, 1H), 2.01-1.58 (m, 6H). MS(ES⁺, m/z): 319.0 (M⁺+1, 100.0).

Example 4 Synthesis of3-bromo-N-(cyclobutylmethyl)-N-(1-phenylethyl)-1H-pyrazole-5-carboxamide

To a solution of 3-bromo-1H-pyrazole-5-carboxylic acid (0.100 g, 0.524mmol) and 4-(((cyclobutylmethyl)amino)methyl)-3-fluorophenol (0.099 g,0.524 mmol) in DMF (1 mL) was added EDCI (0.151 g, 0.785 mmol), HOAt(0.106 g, 0.785 mmol) and 4-methylmorpholine (0.159 g, 1.571 mmol). Thenthe reaction mixture was stirred at r.t. overnight. The resultingreaction mixture was diluted with 30 mL DCM and washed with water 20 mL.The aqueous layer was extracted with three 15 mL portions of methylenechloride. The combined organic extracts were washed with 10 mL of brine,dried with Na₂SO₄ and concentrated. The residue was purified bychromatography on silica gel eluting with 0 to 15% methanol in methylenechloride to give (0.065 g, 0.179 mmol, 34% yield) of compound3-bromo-N-(cyclobutylmethyl)-N-(1-phenylethyl)-1H-pyrazole-5-carboxamide.

¹H-NMR (CD₃OD/400 MHz): 7.34 (m, 5H), 6.60 (s, 1H), 5.60 (m, 1H), 4.80(m, 1H), 3.40 (m, 2H), 2.40 (m, 1H), 2.01-1.58 (m, 6H). MS (ES⁺, m/z):361.9 (M⁺+1, 100.0).

Example 5 Synthesis of3-trifluoromethyl-N-(cyclobutylmethyl)-N-(1-phenylethyl)-1H-pyrazole-5-carboxamide

To a solution of 3-trifluoromethyl-1H-pyrazole-5-carboxylic acid (0.100g, 0.524 mmol) and 4-(((cyclobutylmethyl)amino)methyl)-3-fluorophenol(0.099 g, 0.524 mmol) in DMF (1 mL) was added EDCI (0.151 g, 0.785mmol), HOAt (0.106 g, 0.785 mmol) and 4-methylmorpholine (0.159 g, 1.571mmol). Then the reaction mixture was stirred at r.t. overnight. Theresulting reaction mixture was diluted with 30 mL DCM and washed withwater 20 mL. The aqueous layer was extracted with three 15 mL portionsof methylene chloride. The combined organic extracts were washed with 10mL of brine, dried with Na₂SO₄ and concentrated. The residue waspurified by chromatography on silica gel eluting with 0 to 15% methanolin methylene chloride to give (0.065 g, 0.179 mmol, 34% yield) ofcompound3-trifluoromethyl-N-(cyclobutylmethyl)-N-(1-phenylethyl)-1H-pyrazole-5-carboxamide.

¹H-NMR (CD₃OD/400 MHz): 7.40 (m, 5H), 6.80 (s, 1H), 5.48 (m, 2H), 3.50(m, 2H), 2.34 (m, 1H), 2.01-1.58 (m, 6H). MS (ES⁺, m/z): 352.0 (M⁺+1,100.0).

Example 6 Synthesis ofN-((1H-indol-4-yl)methyl)-N-(cyclobutylmethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

To a solution of 1H-indole-4-carbaldehyde (1.5 g, 10.33 mmol) andcyclobutylmethanamine hydrogen chloride (1.26 g, 10.33 mmol) inmethylene chloride (10 mL) was added MgSO₄ (3.73 g, 31.0 mmol) andNa₂CO₃ (2.19 g, 10.33 mmol). The mixture was stirred at room temperatureovernight, and then NaBH₄ (0.39 g, 10.33 mmol) was added and stirredadditional 16 h. It was quenched with methanol and diluted with 30 mLmethylene chloride, and washed with water 20 mL. The aqueous layer wasextracted with three 20 mL portions of methylene chloride. The combinedorganic extracts were washed with 20 mL of brine, dried with Na₂SO₄ andconcentrated. The residue was purified by chromatography on silica geleluting with 0 to 10% methanol in methylene chloride to give (1.8 g,8.40 mmol, 81% yield) of compoundN-((1H-indo-4-yl)methyl)-1-cyclobutylmethanamine.

¹H-NMR (CD₃OD/400 MHz): 7.30 (d, J=8.0 Hz, 1H), 7.24 (d, J=3.2 Hz, 1H),7.07 (t, J=8.0 Hz, 1H), 6.96 (d, J=6.8 Hz, 1H), 6.52 (m, 1H), 3.99 (s,2H), 2.54 (d, J=7.6 Hz, 2H), 2.50 (m, 1H), 2.10 (m, 2H), 1.80 (m, 2H),1.65 (m, 2H). MS (ES⁺, m/z): 215.0 (M⁺+1, 100.0).

To a solution of 3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (0.1g, 0.555 mmol) and N((1H-indo-4-yl)methyl)-1-cyclobutylmethanamine(0.119 g, 0.555 mmol) in DMF (1 mL) was added EDCI (0.160 g, 0.833mmol), HOAt (0.133 g, 0.833 mmol) and 4-methylmorpholine (0.168 g, 1.666mmol). Then the reaction mixture was stirred at r.t. overnight. Theresulting reaction mixture was diluted with 30 mL DCM and washed withwater 20 mL. The aqueous layer was extracted with three 15 mL portionsof methylene chloride. The combined organic extracts were washed with 10mL of brine, dried with Na₂SO₄ and concentrated. The residue waspurified by chromatography on silica gel eluting with 0 to 15% methanolin methylene chloride to give (0.160 g, 0.425 mmol, 77% yield) ofcompoundN-((1H-indol-4-yl)methyl)-N-(cyclobutylmethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

¹H-NMR (CDCl₃/400 MHz; stable amide rotamers were observed by NMR): 7.35(m, 1H), 7.24 (br, 1H), 7.10 (m, 1H), 6.97 (m, 0.5H), 6.84 (m, 1H), 6.60(m, 0.5H), 6.50 (m, 0.5H), 6.39 (m, 0.5H), 5.05 (s, 2H), 3.60 (s, 1H),3.34 (s, 1H), 2.74 (m, 1H), 2.50-1.55 (m, 6H). MS (ES⁺, m/z): 377.0(M⁺+1, 100.0).

Example 7 Synthesis of3-trifluoromethyl-N-(cyclobutylmethyl)-N-((2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)methyl)-1H-pyrazole-5-carboxamide

To a solution of 3-trifluoromethyl-1H-pyrazole-5-carboxylic acid (0.055g, 0.403 mmol) and7-(((cyclobutylmethyl)amino)methyl)benzo[d]thiazol-2(3H)-one (0.10 g,0.403 mmol) in DMF (1 mL) was added EDCI (0.116 g, 0.604 mmol), HOAt(0.082 g, 0.604 mmol) and 4-methylmorpholine (0.122 g, 1.208 mmol). Thenthe reaction mixture was stirred at r.t. overnight. The resultingreaction mixture was diluted with 30 mL DCM and washed with water 20 mL.The aqueous layer was extracted with three 15 mL portions of methylenechloride. The combined organic extracts were washed with 10 mL of brine,dried with Na₂SO₄ and concentrated. The residue was purified bychromatography on silica gel eluting with 0 to 15% methanol in methylenechloride to give (0.060 g, 0.163 mmol, 41% yield) of compound3-trifluoromethyl-N-(cyclobutylmethyl)-N-((2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)methyl)-1H-pyrazole-5-carboxamide.

¹H-NMR (CD₃OD/400 MHz): 7.31 (m, 1H), 7.04 (m, 3H), 5.04 (m, 1H), 5.04(m, 1H), 3.70 (m, 1H), 3.50 (m, 1H), 2.56 (m, 1H), 2.00-1.56 (m, 6H). MS(ES⁺, m/z): 368.0 (M⁺+1, 100.0).

Example 8 Synthesis of3-cyano-N-(cyclobutylmethyl)-N-((2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)methyl)-1H-pyrazole-5-carboxamide

To a solution of 3-cyano-1H-pyrazole-5-carboxylic acid (0.055 g, 0.403mmol) and 7-(((cyclobutylmethyl)amino)methyl)benzo[d]thiazol-2(3H)-one(0.10 g, 0.403 mmol) in DMF (1 mL) was added EDCI (0.116 g, 0.604 mmol),HOAt (0.082 g, 0.604 mmol) and 4-methylmorpholine (0.122 g, 1.208 mmol).Then the reaction mixture was stirred at r.t. overnight. The resultingreaction mixture was diluted with 30 mL DCM and washed with water 20 mL.The aqueous layer was extracted with three 15 mL portions of methylenechloride. The combined organic extracts were washed with 10 mL of brine,dried with Na₂SO₄ and concentrated. The residue was purified bychromatography on silica gel eluting with 0 to 15% methanol in methylenechloride to give (0.060 g, 0.163 mmol, 41% yield) of compound3-cyano-N-(cyclobutylmethyl)-N-((2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)methyl)-1H-pyrazole-5-carboxamide.

¹H-NMR (CD₃OD/400 MHz): 7.31 (m, 1H), 7.04 (m, 3H), 5.04 (m, 1H), 5.04(m, 1H), 3.70 (m, 1H), 3.50 (m, 1H), 2.56 (m, 1H), 2.00-1.56 (m, 6H). MS(ES⁺, m/z): 368.0 (M⁺+1, 100.0).

Example 9 Synthesis of3-chloro-N-(cyclobutylmethyl)-N-((2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)methyl)-1H-pyrazole-5-carboxamide

To a solution of 2-oxo-2,3-dihydrobenzo[d]thiazole-7-carbaldehyde (0.4g, 2.32 mmol) and cyclobutylmethanamine hydrogen chloride (0.190 g, 2.32mmol) in methylene chloride (5 mL) was added MgSO₄ (0.81 g, 6.70 mmol)and Na₂CO₃ (0.47 g, 4.46 mmol). The mixture was stirred at roomtemperature overnight, and then NaBH₄ (0.084 g, 2.23 mmol) was added andstirred additional 16 h. It was quenched with methanol and diluted with20 mL methylene chloride, and washed with water 10 mL. The aqueous layerwas extracted with three 15 mL portions of methylene chloride. Thecombined organic extracts were washed with 10 mL of brine, dried withNa₂SO₄ and concentrated. The residue was purified by chromatography onsilica gel eluting with 0 to 10% methanol in methylene chloride to give(0.45 g, 1.812 mmol, 81% yield) of compound7-(((cyclobutylmethyl)amino)methyl)benzo[d]thiazol-2(3H)-one.

To a solution of 3-chloro-1H-pyrazole-5-carboxylic acid (0.1 g, 0.682mmol) and 7-(((cyclobutylmethyl)amino)methyl)benzo[d]thiazol-2(3H)-one(0.169 g, 0.682 mmol) in DMF (1 mL) was added EDCI (0.196 g, 1.024mmol), HOAt (0.138 g, 1.024 mmol) and 4-methylmorpholine (0.207 g, 2.047mmol). Then the reaction mixture was stirred at r.t. overnight. Theresulting reaction mixture was diluted with 30 mL DCM and washed withwater 20 mL. The aqueous layer was extracted with three 15 mL portionsof methylene chloride. The combined organic extracts were washed with 10mL of brine, dried with Na₂SO₄ and concentrated. The residue waspurified by chromatography on silica gel eluting with 0 to 15% methanolin methylene chloride to give (0.045 g, 0.119 mmol, 16% yield) ofcompound3-Chloro-N-(cyclobutylmethyl)-N-((2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)methyl)-1H-pyrazole-5-carboxamide.

¹H-NMR (CD₃OD/400 MHz): 7.30 (m, 1H), 7.10 (m, 2H), 6.50 (m, 1H), 4.77(m, 2H), 3.53 (m, 2H), 2.66 (m, 1H), 2.00-1.59 (m, 6H). MS (ES⁺, m/z):377.0 (M⁺+1, 100.0).

Example 10 Synthesis of3-bromo-N-(cyclobutylmethyl)-N-((2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)methyl)-1H-pyrazole-5-carboxamide

To a solution of 3-bromo-1H-pyrazole-5-carboxylic acid (0.077 g, 0.403mmol) and 7-(((cyclobutylmethyl)amino)methyl)benzo[d]thiazol-2(3H)-one(0.10 g, 0.403 mmol) in DMF (1 mL) was added EDCI (0.116 g, 0.604 mmol),HOAt (0.082 g, 0.604 mmol) and 4-methylmorpholine (0.122 g, 1.208 mmol).Then the reaction mixture was stirred at r.t. overnight. The resultingreaction mixture was diluted with 30 mL DCM and washed with water 20 mL.The aqueous layer was extracted with three 15 mL portions of methylenechloride. The combined organic extracts were washed with 10 mL of brine,dried with Na₂SO₄ and concentrated. The residue was purified bychromatography on silica gel eluting with 0 to 15% methanol in methylenechloride to give (0.020 g, 0.047 mmol, 12% yield) of compound3-bromo-N-(cyclobutylmethyl)-N-((2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)methyl)-1H-pyrazole-5-carboxamide.

¹H-NMR (CD₃OD/400 MHz): 7.30 (m, 1H), 7.06 (m, 2H), 6.50 (m, 1H), 4.77(m, 2H), 3.53 (m, 2H), 2.66 (m, 1H), 2.00-1.59 (m, 6H). MS (ES⁺, m/z):420.9 (M⁺+1, 100.0).

Example 11 Synthesis ofN-(azetidin-3-ylmethyl)-3-bromo-N-(2-fluoro-4-hydroxybenzyl)-1H-pyrazole-5-carboxamide

To a solution of 2-fluoro-4-hydroxybenzaldehyde (0.226 g, 1.611 mmol)and tert-butyl 3-(aminomethyl)azetidine-1-carboxylate (0.300 g, 1.611mmol) in methylene chloride (5 mL) was added MgSO₄ (0.582 g, 4.83 mmol).The mixture was stirred at room temperature overnight, and then NaBH₄(0.061 g, 1.611 mmol) was added and stirred additional 16 h. It wasquenched with methanol and diluted with 20 mL methylene chloride, andwashed with water 10 mL. The aqueous layer was extracted with three 15mL portions of methylene chloride. The combined organic extracts werewashed with 10 mL of brine, dried with Na₂SO₄ and concentrated. Theresidue was purified by chromatography on silica gel eluting with 0 to10% methanol in methylene chloride to give (0.399 g, 1.29 mmol, 80%yield) of compound tert-butyl3-(((2-fluoro-4-hydroxybenzyl)amino)methyl)azetidine-1-carboxylate.

To a solution of 3-bromo-1H-pyrazole-5-carboxylic acid (0.038 g, 0.161mmol) and tert-butyl4-(((cyclobutylmethyl)amino)methyl)indoline-1-carboxylate (0.050 g,0.161 mmol) in DMF (1 mL) was added EDCI (0.037 g, 0.193 mmol), HOAt(0.022 g, 0.161 mmol) and 4-methylmorpholine (0.081 g, 0.81 mmol). Thenthe reaction mixture was stirred at r.t. overnight. The resultingreaction mixture was diluted with 30 mL DCM and washed with water 20 mL.The aqueous layer was extracted with three 15 mL portions of methylenechloride. The combined organic extracts were washed with 10 mL of brine,dried with Na₂SO₄ and concentrated. The residue was used for the nextstep directly without further purification.

To a solution of tert-butyl3-((3-bromo-N-(2-fluoro-4-hydroxybenzyl)-1H-pyrazole-5-carboxamido)methyl)azetidine-1-carboxylate(0.02 g, 0.041 mmol) in DCM (2 mL) was added Et₃SiH (0.5 mL), and TFA(0.5 mL). Then the reaction mixture was stirred at r.t. overnight. Theresulting reaction mixture was evaporated and the residue was dilutedwith 30 mL DCM and washed with saturated NaHCO₃ 20 mL. The aqueous layerwas extracted with three 15 mL portions of methylene chloride. Thecombined organic extracts were washed with 10 mL of brine, dried withNa₂SO₄ and concentrated. The residue was purified by chromatography onsilica gel eluting with 0 to 15% methanol in methylene chloride to give(0.010 g, 0.026 mmol, 63% yield) of compoundN-(azetidin-3-ylmethyl)-3-bromo-N-(2-fluoro-4-hydroxybenzyl)-1H-pyrazole-5-carboxamide.

¹H-NMR (CD₃OD/400 MHz): 7.06 (m, 1H), 6.60 (m, 3H), 4.80 (m, 2H), 4.00(m, 4H), 3.75 (m, 2H), 3.10 (m, 1H). MS (ES⁺, m/z): 382.9 (M⁺+1, 100.0).

Example 14 Synthesis of tert-butyl4-((N-(cyclobutylmethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)methyl)indoline-1-carboxylate

To a solution of tert-butyl 4-formylindoline-1-carboxylate (0.5 g, 2.02mmol) and cyclobutylmethanamine hydrogen chloride (0.172 g, 2.02 mmol)in methylene chloride (5 mL) was added MgSO₄ (0.730 g, 6.07 mmol) andNa₂CO₃ (0.43 g, 4.04 mmol). The mixture was stirred at room temperatureovernight, and then NaBH₄ (0.076 g, 2.02 mmol) was added and stirredadditional 16 h. It was quenched with methanol and diluted with 20 mLmethylene chloride, and washed with water 10 mL. The aqueous layer wasextracted with three 15 mL portions of methylene chloride. The combinedorganic extracts were washed with 10 mL of brine, dried with Na₂SO₄ andconcentrated. The residue was purified by chromatography on silica geleluting with 0 to 10% methanol in methylene chloride to give (0.4 g,1.26 mmol, 63% yield) of compound tert-butyl4-(((cyclobutylmethyl)amino)methyl)indoline-1-carboxylate.

¹H-NMR (CD₃OD/400 MHz): 7.12 (m, 2H), 6.92 (m, 1H), 3.96 (m, 2H), 3.64(s, 2H), 2.50 (m, 1H), 2.20 (m, 2H), 1.80 (m, 2H), 1.60 (m, 2H), 1.55(s, 9H). MS (ES⁺, m/z): 317.0 (M⁺+1, 100.0).

To a solution of 3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (0.06g, 0.333 mmol) and tert-butyl4-(((cyclobutylmethyl)amino)methyl)indoline-1-carboxylate (0.105 g,0.333 mmol) in DMF (1 mL) was added EDCI (0.096 g, 0.500 mmol), HOAt(0.068 g, 0.500 mmol) and 4-methylmorpholine (0.101 g, 1.00 mmol). Thenthe reaction mixture was stirred at r.t. overnight. The resultingreaction mixture was diluted with 30 mL DCM and washed with water 20 mL.The aqueous layer was extracted with three 15 mL portions of methylenechloride. The combined organic extracts were washed with 10 mL of brine,dried with Na₂SO₄ and concentrated. The residue was purified bychromatography on silica gel eluting with 0 to 15% methanol in methylenechloride to give (0.080 g, 0.167 mmol, 50% yield) of compound tert-butyl4-4N-(cyclobutylmethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)methyl)indoline-1-carboxylate.

¹H-NMR (CD₃OD/400 MHz): 7.22 (m, 1H), 7.15 (m, 1H), 6.75 (m, 1H), 6.67(m, 0.5H), 6.41 (m, 0.5H), 4.68 (m, 2H), 4.00 (m, 2H), 3.55 (m, 2H),3.00 (m, 2H), 2.65 (m, 1H), 2.03-1.70 (m, 6H), 1.55 (s, 9H). MS (ES⁺,m/z): 479.1 (M⁺+1, 100.0).

To a solution of tert-butyl4-((N-(cyclobutylmethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)methyl)indoline-1-carboxylate(0.1 g, 0.555 mmol) in DCM (2 mL) was added Et₃SiH (0.5 mL), and TFA(0.5 mL). Then the reaction mixture was stirred at r.t. overnight. Theresulting reaction mixture was evaporated and the residue was dilutedwith 30 mL DCM and washed with saturated NaHCO₃ 20 mL. The aqueous layerwas extracted with three 15 mL portions of methylene chloride. Thecombined organic extracts were washed with 10 mL of brine, dried withNa₂SO₄ and concentrated. The residue was purified by chromatography onsilica gel eluting with 0 to 15% methanol in methylene chloride to give(0.030 g, 0.079 mmol, 95% yield) of compoundN-(cyclobutylmethyl)-N-(indolin-4-ylmethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

¹H-NMR (CD₃OD/400 MHz): 7.37 (m, 2H), 6.95 (m, 1H), 6.55 (m, 1H), 4.60(m, 2H), 3.80 (m, 2H), 3.60 (m, 2H), 3.30 (m, 2H), 2.70 (m, 1H),2.03-1.50 (m, 6H). MS (ES⁺, m/z): 379.0 (M⁺+1, 100.0).

Example 47 Synthesis ofN-(2-fluorobenzyl)-N-(trans-4-methoxycyclohexyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

To a solution of 2-fluorobenzaldehyde (0.077 g, 0.619 mmol) andtrans-4-methoxycyclohexanamine (0.08 g, 0.619 mmol) in methylenechloride (5 mL) was added MgSO₄ (0.224 g, 1.858 mmol). The mixture wasstirred at room temperature overnight, and then NaBH₄ (0.023 g, 0.619mmol) was added and stirred additional 16 h. It was quenched withmethanol and diluted with 20 mL methylene chloride, and washed withwater 10 mL. The aqueous layer was extracted with three 15 mL portionsof methylene chloride. The combined organic extracts were washed with 10mL of brine, dried with Na₂SO₄ and concentrated. The residue was usedfor the next step without further purification.

To a solution of 3-trifluoro-1H-pyrazole-5-carboxylic acid (0.112 g,0.620 mmol) and N-(2-fluorobenzyl)-4-methoxycyclohexanamine (0.147 g,0.620 mmol) in ACN (5 mL) was added T3P (Propylphosphonic anhydridesolution, 50 wt % in ethyl acetate) (0.207 g, 0.651 mmol) and TEA (0.501g). Then the reaction mixture was stirred at r.t. for 1 day. Theresulting reaction mixture was diluted with 30 mL DCM and washed withwater 10 mL. The DCM phase was dried with Na₂SO₄ and evaporated.Preparative HPLC purification provided pure product (0.032 g, 0.079mmol, 13% yield). ¹H-NMR (CD₃OD/400 MHz): 7.33 (m, 2H), 7.12 (m, 2H),6.90 (m, 1H), 4.81 (m, 2H), 4.20 (m, 1H), 3.14 (m, 1H), 2.09 (m, 2H),1.82 (m, 2H), 1.66 (m, 2H), 1.21 (m, 2H). MS (ES⁺, m/z): 400.4 (M⁺+1,100.0).

Compounds in Examples 29-46, 48-53, 55 and 56 were prepared in a manneranalagous to that described in Example 47.

Example 54 Synthesis of tert-butyl(3-((N-(trans-4-methoxycyclohexyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)methyl)phenyl)carbamate

To a solution of tert-butyl (3-formylphenyl)carbamate (0.137 g, 0.619mmol) and trans-4-methoxycyclohexanamine (0.08 g, 0.619 mmol) inmethylene chloride (5 mL) was added MgSO₄ (0.224 g, 1.858 mmol). Themixture was stirred at room temperature overnight, and then NaBH₄ (0.023g, 0.619 mmol) was added and stirred additional 16 h. It was quenchedwith methanol and diluted with 20 mL methylene chloride, and washed withwater 10 mL. The aqueous layer was extracted with three 15 mL portionsof methylene chloride. The combined organic extracts were washed with 10mL of brine, dried with Na₂SO₄ and concentrated. The residue was usedfor the next step without further purification.

To a solution of 3-trifluoro-1H-pyrazole-5-carboxylic acid (0.111 g,0.619 mmol) and tert-butyl(3-(((trans-4-methoxycyclohexyl)amino)methyl)phenyl)carbamate (0.207 g,0.619 mmol) in ACN (5 mL) was added T3P (Propylphosphonic anhydridesolution, 50 wt % in ethyl acetate) (0.207 g, 0.650 mmol) and TEA (0.500g). Then the reaction mixture was stirred at r.t. for 1 day. Theresulting reaction mixture was diluted with 30 mL DCM and washed withwater 10 mL. The DCM phase was dried with Na₂SO₄ and evaporated. Withoutpurification, the residue was dissolved in DCM (2 mL) and TFA (0.5 mL)was added. Then the reaction mixture was stirred at r.t. overnight. Theresulting reaction mixture was evaporated and the residue was dilutedwith 30 mL DCM and washed with saturated NaHCO₃ 20 mL. The aqueous layerwas extracted with three 15 mL portions of methylene chloride. Thecombined organic extracts were washed with 10 mL of brine, dried withNa₂SO₄ and concentrated. Preparative HPLC purification provided pureproduct tert-butyl(3-((N-((trans-4-methoxycyclohexyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)methyl)phenyl)carbamate(0.030 g, 0.076 mmol, 12% yield).

¹H-NMR (CD₃OD/400 MHz): 7.45 (m, 1H), 7.27 (m, 3H), 6.80 (m, 1H), 4.80(m, 2H), 4.22 (m, 1H), 3.25 (s, 3H), 3.05 (m, 1H), 2.05 (m, 2H), 1.84(m, 2H), 1.66 (m, 2H), 1.20 (m, 2H).). MS (ES⁺, m/z): 397.5 (M⁺+1,100.0).

Compounds in Examples 57, 77, 95 and 97 were prepared in a manneranalagous to that described in Example 54.

Example 59 Synthesis ofN-(2-(1,4-dioxaspiro[4.5]decan-8-yl)ethyl)-N-(2-fluorobenzyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

To a solution of 2-fluorobenzaldehyde (0.134 g, 1.080 mmol) and2-(1,4-dioxaspiro[4.5]decan-8-yl)ethanamine (0.2 g, 1.080 mmol) inmethylene chloride (5 mL) was added MgSO₄ (0.390 g, 3.24 mmol). Themixture was stirred at room temperature overnight, and then NaBH₄ (0.041g, 1.080 mmol) was added and stirred additional 16 h. It was quenchedwith methanol and diluted with 20 mL methylene chloride, and washed withwater 10 mL. The aqueous layer was extracted with three 15 mL portionsof methylene chloride. The combined organic extracts were washed with 10mL of brine, dried with Na₂SO₄ and concentrated. The residue was usedfor the next step without further purification.

To a solution of 3-trifluoro-1H-pyrazole-5-carboxylic acid (0.194 g,1.080 mmol) andN-(2-fluorobenzyl)-2-(1,4-dioxaspiro[4.5]decan-8-yl)ethanamine (0.317 g,1.080 mmol) in ACN (5 mL) was added T3P (Propylphosphonic anhydridesolution, 50 wt % in ethyl acetate) (0.361 g, 1.134 mmol) and TEA (0.873g). Then the reaction mixture was stirred at r.t. for 1 day. Theresulting reaction mixture was diluted with 30 mL DCM and washed withwater 10 mL. The DCM phase was dried with Na₂SO₄ and evaporated.Preparative HPLC purification provided pure product (0.160 g, 0.351mmol, 33% yield). ¹H-NMR (CD₃CN/400 MHz): 7.35 (m, 2H), 7.16 (m, 2H),6.80 (m, 1H), 4.77 (m, 2H), 3.85 (m, 4H), 3.52 (m, 2H), 2.30 (m, 2H),1.62 (m, 5H), 1.17 (m, 4H). MS (ES⁺, m/z): 456.5 (M⁺+1, 100.0).

Example 60 Synthesis ofN-(2-(1,4-dioxaspiro[4.5]decan-8-yl)ethyl)-N-(2-fluorobenzyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

To a solution ofN-(2-(1,4-dioxaspiro[4.5]decan-8-yl)ethyl)-N-(2-fluorobenzyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(0.492 g, 1.080 mmol) in DCM (2 mL) was added TFA (0.5 mL). Then thereaction mixture was stirred at r.t. overnight. The resulting reactionmixture was evaporated and the residue was diluted with 30 mL DCM andwashed with saturated NaHCO₃ 20 mL. The aqueous layer was extracted withthree 15 mL portions of methylene chloride. The combined organicextracts were washed with 10 mL of brine, dried with Na₂SO₄ andconcentrated. The residue was purified by chromatography on silica geleluting with 0 to 15% methanol in methylene chloride to give (0.200 g,0.486 mmol, 45% yield) of compoundN-(2-fluorobenzyl)-N-(2-(4-oxocyclohexyl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

¹H-NMR (CDCl₃/400 MHz): 7.35 (m, 1H), 7.18 (m, 3H), 6.70 (m, 1H), 4.87(m, 2H), 3.59 (m, 2H), 2.28 (m, 4H), 2.04 (m, 2H), 1.70 (m, 3H), 1.44(m, 2H). MS (ES⁺, m/z): 412.5 (M⁺+1, 100.0).

Example 62 Synthesis ofN-(2-chlorobenzyl)-N-(2-(1,1-dioxidotetrahydrothiophen-3-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

To a solution of 2-chorobenzaldehyde (0.086 g, 0.613 mmol) and3-(2-aminoethyl)tetrahydrothiophene 1,1-dioxide (0.10 g, 0.613 mmol) inmethylene chloride (5 mL) was added MgSO₄ (0.221 g, 1.838 mmol). Themixture was stirred at room temperature overnight, and then NaBH₄ (0.023g, 0.613 mmol) was added and stirred additional 16 h. It was quenchedwith methanol and diluted with 20 mL methylene chloride, and washed withwater 10 mL. The aqueous layer was extracted with three 15 mL portionsof methylene chloride. The combined organic extracts were washed with 10mL of brine, dried with Na₂SO₄ and concentrated. The residue was usedfor the next step without further purification.

To a solution of 3-trifluoro-1H-pyrazole-5-carboxylic acid (0.110 g,0.613 mmol) and 3-(2-((2-chlorobenzyl)amino)ethyl)tetrahydrothiophene1,1-dioxide (0.176 g, 0.613 mmol) in ACN (5 mL) was added T3P(Propylphosphonic anhydride solution, 50 wt % in ethyl acetate) (0.205g, 0.644 mmol) and TEA (0.495 g). Then the reaction mixture was stirredat r.t. for 1 day. The resulting reaction mixture was diluted with 30 mLDCM and washed with water 10 mL. The DCM phase was dried with Na₂SO₄ andevaporated. Preparative HPLC purification provided pure productN-(2-chlorobenzyl)-N-(2-(1,1-dioxidotetrahydrothiophen-3-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(0.040 g, 0.087 mmol, 14% yield).

¹H-NMR (DMSO-d₆/400 MHz): 7.46 (m, 1H), 7.35 (m, 3H), 6.85 (m, 1H), 4.91(m, 2H), 3.60 (m, 2H), 3.10 (m, 2H), 2.72 (m, 1H), 2.41 (m, 2H), 1.85(m, 2H). MS (ES⁺, m/z): 450.4 (M⁺+1, 100.0).

Compounds in Examples 55, 56, 61, 63-72, 76, 88-90, 92, 93, 100 and 111were prepared in a manner analagous to that described in Example 62.

Example 73 Synthesis ofN-(2-chlorobenzyl)-N-(2-(1,1-dioxidotetrahydrothiophen-3-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

To a solution of 2-chorobenzaldehyde (0.194 g, 1.377 mmol) and2-(tetrahydro-2H-thiopyran-4-yl)ethanamine (0.20 g, 1.377 mmol) inmethylene chloride (5 mL) was added MgSO₄ (0.497 g, 4.13 mmol). Themixture was stirred at room temperature overnight, and then NaBH₄ (0.052g, 1.377 mmol) was added and stirred additional 16 h. It was quenchedwith methanol and diluted with 20 mL methylene chloride, and washed withwater 10 mL. The aqueous layer was extracted with three 15 mL portionsof methylene chloride. The combined organic extracts were washed with 10mL of brine, dried with Na₂SO₄ and concentrated. The residue was usedfor the next step without further purification.

To a solution of 3-trifluoro-1H-pyrazole-5-carboxylic acid (0.248 g,1.377 mmol) andN-(2-chlorobenzyl)-2-(tetrahydro-2H-thiopyran-4-yl)ethanamine (0.372 g,1.377 mmol) in ACN (5 mL) was added T3P (Propylphosphonic anhydridesolution, 50 wt % in ethyl acetate) (0.460 g, 1.466 mmol) and TEA (0.495g). Then the reaction mixture was stirred at r.t. for 1 day. Theresulting reaction mixture was diluted with 30 mL DCM and washed withwater 10 mL. The DCM phase was dried with Na₂SO₄ and evaporated.Preparative HPLC purification provided pure productN-(2-chlorobenzyl)-N-(2-(tetrahydro-2H-thiopyran-4-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(0.060 g, 0.139 mmol, 10% yield).

¹H-NMR (Acetone-d₆/400 MHz): 7.41 (m, 4H), 6.80 (m, 1H), 4.95 (d, 2H),3.61 (d, 2H), 2.60 (m, 4H), 1.99 (m, 1H), 1.61 (m, 2H), 1.30 (m, 4H). MS(ES⁺, m/z): 432.4 (M⁺+1, 100.0).

Compounds in Examples 79, 80, 82, 84, 86 were prepared in a manneranalagous to that described in Example 73.

Example 74 Synthesis ofN-(2-chlorobenzyl)-N-(2-(1-oxidotetrahydro-2H-thiopyran-4-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

To a solution ofN-(2-chlorobenzyl)-N-(2-(tetrahydro-2H-thiopyran-4-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(0.015 g, 0.035 mmol) in ACN (1 mL) was added t-BuOOH (3.13 mg, 0.035mmol). Then the reaction mixture was stirred at r.t. for 1 day. Theresulting reaction mixture was diluted with 30 mL DCM and washed withsaturated Na₂S₂O₃ aqueous solution 10 mL. The DCM phase was dried withNa₂SO₄ and evaporated. Preparative HPLC purification provided pureproductN-(2-chlorobenzyl)-N-(2-(tetrahydro-2H-thiopyran-4-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(0.010 g, 0.022 mmol, 64% yield).

¹H-NMR (Acetone-d₆/400 MHz): 7.41 (m, 4H), 6.90 (m, 1H), 4.95 (d, 2H),3.61 (d, 2H), 3.16 (m, 2H), 2.81 (m, 1H), 2.53 (m, 2H), 2.08 (m, 2H),1.73 (m, 4H). MS (ES⁺, m/z): 448.4 (M⁺+1, 100.0).

Example 75 Synthesis ofN-(2-chlorobenzyl)-N-(2-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

To a solution ofN-(2-chlorobenzyl)-N-(2-(tetrahydro-2H-thiopyran-4-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(0.015 g, 0.035 mmol) in ACN (1 mL) was added H₂O₂ (1.18 mg, 0.035 mmol)and ammonium molybdate (NH₄)₂MoO₄ (0.1 eq., 1.0 mg). Then the reactionmixture was stirred at r.t. for 1 day. The resulting reaction mixturewas diluted with 30 mL DCM and washed with saturated Na₂S₂O₃ aqueoussolution 10 mL. The DCM phase was dried with Na₂SO₄ and evaporated.Preparative HPLC purification provided pure productN-(2-chlorobenzyl)-N-(2-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(0.012 g, 0.026 mmol, 75% yield).

¹H-NMR (CD₃CN/400 MHz): 7.47 (m, 1H), 7.32 (m, 3H), 6.90 (m, 1H), 4.85(m, 2H), 3.49 (m, 2H), 2.90 (m, 4H), 2.25 (m, 2H), 2.05 (m, 1H), 1.61(m, 4H). MS (ES⁺, m/z): 464.4 (M⁺+1, 100.0).

Compounds in Examples 78, 81, 83, 85, 87 were prepared in a manneranalagous to that described in Example 75.

Example 91 Synthesis ofN-(2-amino-6-fluorobenzyl)-N-(2-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

To a solution of tert-butyl (3-fluoro-2-formylphenyl)carbamate (0.132 g,0.551 mmol) and 2-(tetrahydro-2H-thiopyran-4-yl)ethanamine (0.08 g,0.551 mmol) in methylene chloride (5 mL) was added MgSO₄ (0.199 g, 1.65mmol). The mixture was stirred at room temperature overnight, and thenNaBH₄ (0.021 g, 0.551 mmol) was added and stirred additional 16 h. Itwas quenched with methanol and diluted with 20 mL methylene chloride,and washed with water 10 mL. The aqueous layer was extracted with three15 mL portions of methylene chloride. The combined organic extracts werewashed with 10 mL of brine, dried with Na₂SO₄ and concentrated. Theresidue was used for the next step without further purification.

To a solution of 3-trifluoro-1H-pyrazole-5-carboxylic acid (0.099 g,0.551 mmol) and tert-butyl(3-fluoro-2-(((2-(tetrahydro-2H-thiopyran-4-yl)ethyl)amino)methyl)phenyl)carbamate(0.203 g, 0.551 mmol) in ACN (5 mL) was added T3P (Propylphosphonicanhydride solution, 50 wt % in ethyl acetate) (0.184 g, 0.579 mmol) andTEA (0.445 g). Then the reaction mixture was stirred at r.t. for 1 day.The resulting reaction mixture was diluted with 30 mL DCM and washedwith water 10 mL. The DCM phase was dried with Na₂SO₄ and evaporated.Preparative HPLC purification provided pure product tert-butyl(3-fluoro-2-((N-(2-(tetrahydro-2H-thiopyran-4-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)methyl)phenyl)carbamate(0.080 g, 0.151 mmol, 27% yield).

To a solution of tert-butyl(3-fluoro-2-((N-(2-(tetrahydro-2H-thiopyran-4-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)methyl)phenyl)carbamate(0.080 g, 0.151 mmol) in ACN (1 mL) was added H₂O₂ (0.256 g, 7.54 mmol)and ammonium molybdate (NH₄)₂MoO₄ (0.1 eq., 19 mg). Then the reactionmixture was stirred at r.t. for 1 day. The resulting reaction mixturewas diluted with 30 mL DCM and washed with saturated Na₂S₂O₃ aqueoussolution 10 mL. The DCM phase was dried with Na₂SO₄ and evaporated.Preparative HPLC purification provided pure product tert-butyl(2-((N-(2-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)methyl)-3-fluorophenyl)carbamate(0.060 g, 0.107 mmol, 71% yield).

To a solution of tert-butyl(2-((N-(2-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)methyl)-3-fluorophenyl)carbamate(0.050 g, 0.089 mmol) in DCM (2 mL) was added TFA (0.5 mL). Then thereaction mixture was stirred at r.t. overnight. The resulting reactionmixture was evaporated and the residue was diluted with 30 mL DCM andwashed with saturated NaHCO₃ 20 mL. The aqueous layer was extracted withthree 15 mL portions of methylene chloride. The combined organicextracts were washed with 10 mL of brine, dried with Na₂SO₄ andconcentrated. The residue was purified by preparative HPLC to give(0.035 g, 0.076 mmol, 85% yield) of compoundN-(2-amino-6-fluorobenzyl)-N-(2-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

¹H-NMR (CD₃OD/400 MHz): 7.09 (m, 1H), 6.90 (m, 1H), 6.52 (m, 1H), 6.41(m, 1H), 4.84 (m, 2H), 3.50 (m, 4H), 2.80 (m, 5H), 1.55 (m, 4H). MS(ES⁺, m/z): 463.4 (M⁺+1, 100.0).

The compound in Example 97 was prepared in a manner analagous to thatdescribed in Example 91.

Example 94 Synthesis ofN-(2-chloro-3-nitrobenzyl)-N-(2-(1,1-dioxidotetrahydrothiophen-3-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

To a solution of 2-chloro-3-nitrobenzaldehyde (0.171 g, 0.919 mmol) and3-(2-aminoethyl)tetrahydrothiophene 1,1-dioxide (0.150 g, 0.919 mmol) inmethylene chloride (5 mL) was added MgSO₄ (0.332 g, 2.76 mmol). Themixture was stirred at room temperature overnight, and then NaBH₄ (0.035g, 0.919 mmol) was added and stirred additional 16 h. It was quenchedwith methanol and diluted with 20 mL methylene chloride, and washed withwater 10 mL. The aqueous layer was extracted with three 15 mL portionsof methylene chloride. The combined organic extracts were washed with 10mL of brine, dried with Na₂SO₄ and concentrated. The residue was usedfor the next step without further purification.

To a solution of 3-trifluoro-1H-pyrazole-5-carboxylic acid (0.165 g,0.919 mmol) and3-(2-((2-chloro-3-nitrobenzyl)amino)ethyl)tetrahydrothiophene1,1-dioxide (0.306 g, 0.919 mmol) in ACN (5 mL) was added T3P(Propylphosphonic anhydride solution, 50 wt % in ethyl acetate) (0.307g, 0.965 mmol) and TEA (0.743 g). Then the reaction mixture was stirredat r.t. for 1 day. The resulting reaction mixture was diluted with 30 mLDCM and washed with water 10 mL. The DCM phase was dried with Na₂SO₄ andevaporated. Preparative HPLC purification provided pure productN-(2-chloro-3-nitrobenzyl)-N-(2-(1,1-dioxidotetrahydrothiophen-3-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(0.150 g, 0.303 mmol, 33% yield).

¹H-NMR (Acetone-d₆/400 MHz): 8.94 (m, 1H), 7.90 (m, 1H), 7.05 (m, 1H),5.10 (m, 2H), 3.75 (m, 2H), 3.20 (m, 2H), 2.90 (m, 1H), 2.70 (m, 1H),2.40 (m, 2H), 1.80 (m, 3H). MS (ES⁺, m/z): 423.6 (M⁺+1, 100.0).

Example 96 Synthesis ofN-(3-amino-2-chlorobenzyl)-N-(2-(1,1-dioxidotetrahydrothiophen-3-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

To a solution ofN-(2-chloro-3-nitrobenzyl)-N-(2-(1,1-dioxidotetrahydrothiophen-3-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(0.050 g, 0.101 mmol) in ethanol (50 mL) passed through the H-Cube at arate of 1.0 mL/min. The catalyst was Rany-Nickle. The hydrogen pressurewas 50 Psi and the temperature was 50° C. The combined organic solutionwas concentrated and purified by preparative HPLC to give (0.038 g,0.082 mmol, 81% yield) of compoundN-(3-amino-2-chlorobenzyl)-N-(2-(1,1-dioxidotetrahydrothiophen-3-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

¹H-NMR (CD₃CN/400 MHz): 7.06 (m, 1H), 6.80 (m, 1H), 6.56 (m, 1H), 6.47(m, 1H), 4.77 (m, 2H), 3.50 (m, 2H), 3.10 (m, 2H), 2.90 (m, 1H), 2.80(m, 1H), 2.60 (m, 1H), 2.30 (m, 2H), 1.80 (m, 3H). MS (ES⁺, m/z): 465.4(M⁺+1, 100.0).

The compound in Example 58 was prepared in a manner analagous to thatdescribed in Example 96.

Examples 113 to 115 demonstrate exemplary pro-drug approaches utilizingthe phenol as the attachment point for water solubilizing groups.

Example 113 Synthesis of4-((3-chloro-N-(cyclobutylmethyl)-1H-pyrazole-5-carboxamido)methyl)-3-fluorophenyldihydrogen phosphate

To a solution of3-chloro-N-(cyclobutylmethyl)-N-(2-fluoro-4-hydroxybenzyl)-1H-pyrazole-5-carboxamide(0.060 g, 0.178 mmol) and diethylcyano diisopropylphosphoramidite (0.048g, 0.178 mmol, 1.0 equiv) and a solution of 1H-tetrazole in dryacetonitrile (0.037 g, 0.533 mmol, 3 equiv) were added. After 3 h, thesolution was cooled to −20° C. and 70% aqueous tert-butyl hydroperoxide(0.016 g, 0.095 mmol, 1 equiv) was added. After 10 min, an aqueoussolution of 10% Na₂S₂O₃ (2 mL) was added at −20° C. The mixture wassubsequently transferred to a separating funnel, extracted withdichloromethane (6 mL x 2), and washed again with aqueous 10% Na₂S₂O₃ (3mL x 2). The solvent was removed by evaporation under reduced pressureand chromatography purification (ethyl acetate/hexane, 0-15%) providedpure product phosphate (0.050 g, 0.095 mmol, 54% yield).

To a solution of4-((3-chloro-N-(cyclobutylmethyl)-1H-pyrazole-5-carboxamido)methyl)-3-fluorophenylbis(2-cyanoethyl) phosphate (0.020 g, 0.038 mmol) in 1 mL ACN was addedTEA 0.5 mL and TFBSA 0.5 mL. After 24 h, the reaction mixture wasconcentrated. The solvent was removed by evaporation under reducedpressure. Preparative HPLC purification (Water/ACN, 10-100%, 15 min;100%, 5 min.) provide pure product4-((3-chloro-N-(cyclobutylmethyl)-1H-pyrazole-5-carboxamido)methyl)-3-fluorophenyldihydrogen (0.010 g, 0.024 mmol).

¹H-NMR (CD₃OD/400 MHz): δ 7.30 (m, 1H), 7.02 (m, 2H), 6.95 (m, 1H), 4.78(m, 2H), 3.57 (m, 2H), 2.65 (m, 1H), 2.02 (m, 2H), 1.78 (m, 4H). MS(ES⁺, m/z): (M+H)⁺: 418.0.

Example 114(4-((3-chloro-N-(cyclobutylmethyl)-1H-pyrazole-5-carboxamido)methyl)-3-fluorophenoxy)methyldihydrogen phosphate

To a mixture of3-chloro-N-(cyclobutylmethyl)-N-(2-fluoro-4-hydroxybenzyl)-1H-pyrazole-5-carboxamide(0.060 g, 0.178 mmol), sodium hydride (11 mg, 0.444 mmol) andtetra-N-butyl ammonium bromide (0.030 g, 0.037 mmol) in DMF was stirredat rt. for 10 mins. To this mixture was added a solution ofdi-tert-butyl chloromethyl phosphate (0.054 g, 0.207 mmol) in DMF 1 mL.The resulting mixture was stirred at rt for overnight. The reactionmixture was taken into DCM 50 mL and washed with water, brine, driedover sodium sulfate and concentrated. Product was purified by flashchromatography (0-8% methanol/DCM) on silica gel to provide phosphate(0.040 g, 0.071 mmol, 48% yield) as colorless liquid.

To a solution of di-tert-butyl((4-((3-chloro-N-(cyclobutylmethyl)-1H-pyrazole-5-carboxamido)methyl)-3-fluorophenoxy)methyl)phosphate (0.030 g, 0.054 mmol) in 1 mL ACN was added TFA 0.5 mL andEt₃SiH 0.5 mL. After 24 h, the reaction mixture was concentrated. Thesolvent was removed by evaporation under reduced pressure. PreparativeHPLC purification (Water/ACN, 10-100%, 15 min; 100%, 5 min.) providepure product(4-((3-chloro-N-(cyclobutylmethyl)-1H-pyrazole-5-carboxamido)methyl)-3-fluorophenoxy)methyldihydrogen phosphate (0.010 g, 0.022 mmol, 42% yield).

¹H-NMR (CD₃OD/400 MHz): δ 7.20 (m, 1H), 6.95 (m, 2H), 6.55 (m, 1H), 5.60(d, 2H), 4.70 (m, 2H), 3.57 (m, 2H), 2.60 (m, 1H), 2.02-1.80 (m, 6H). MS(ES⁺, m/z): (M+H)⁺: 448.0.

Example 115(S)-4-((3-chloro-N-(cyclobutylmethyl)-1H-pyrazole-5-carboxamido)methyl)-3-fluorophenyl2-amino-2-methylbutanoate

To a solution of4-chloro-N-(cyclobutylmethyl)-N-(2-fluoro-4-hydroxybenzyl)-1H-pyrrole-2-carboxamide(0.040 g, 0.118 mmol) in 3 mL ethyl acetate was added Boc-iso-Valine(0.026 g, 0.118 mmol), DCC (0.037 g, 0.178 mmol) and pyridine 0.5 mL.The reaction mixture was added at r.t. for overnight. After removal ofall the solvent, the residue was purified by chromatography. (0-30%methanol/DCM)(S)-4-((3-chloro-N-(cyclobutylmethyl)-1H-pyrazole-5-carboxamido)methyl)-3-fluorophenyl2-(Boc-amino)-2-methylbutanoate was obtained (0.030 g, 0.056 mmol, 47%yield).

To a solution of(S)-4-((3-chloro-N-(cyclobutylmethyl)-1H-pyrazole-5-carboxamido)methyl)-3-fluorophenyl2-(Boc-amino)-2-methylbutanoate (0.020 g, 0.037 mmol) in ACN 2 mL wasadded 0.5 mL Et₃SiH and 0.5 ml TFA, and then stirred at r.t. forovernight. After removed the solvent, chromatography on silica gel with0-40% methanol in DCM give the crude product. Then, the crude productwas purified one more time by preparative HPLC (Water/ACN,5-100%, 15mins, then 100%, 5 mins.) gave pure product(S)-4-((3-chloro-N-(cyclobutylmethyl)-1H-pyrazole-5-carboxamido)methyl)-3-fluorophenyl2-amino-2-methylbutanoate (0.010 g, 0.023 mmol, 62% yield).

¹H-NMR (CD₃OD/400 MHz): δ 7.34 (m, 1H), 7.05 (m, 2H), 6.55 (m, 1H), 4.95(d, 2H), 3.60 (m, 2H), 2.80 (m, 1H), 2.05 (m, 1H), 2.00 (m, 5H), 1.80(m, 5H), 1.00 (t, 3H). MS (ES⁺, m/z): (M+H)⁺: 437.1.

Examples 116-243

The reductive amination and amide formation were carried out using amethod analogous to that described in Example 1.

Example 116

-   3-chloro-N-(cyclobutylmethyl)-N-((3-fluoropyridin-4-yl)methyl)-1H-pyrazole-5-carboxamide.

Example 119

-   N-((1H-benzo[d]imidazol-4-yl)methyl)-3-chloro-N-(cyclobutylmethyl)-1H-pyrazole-5-carboxamide.

Example 120

-   N-((1H-benzo[d]imidazol-4-yl)methyl)-3-bromo-N-(cyclobutylmethyl)-1H-pyrazole-5-carboxamide.

Example 121

-   3-bromo-N-(cyclobutylmethyl)-N-((3-((methylamino)methyl)-1H-indol-4-yl)methyl)-1H-pyrazole-5-carboxamide.

Example 123

-   N-((1H-benzo[d]imidazol-4-yl)methyl)-N-(cyclobutylmethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 124

-   N-(2-chloro-4-hydroxybenzyl)-N-(cyclobutylmethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 125

-   N-(2-chloro-4-hydroxybenzyl)-3-bromo-N-(cyclobutylmethyl)-1H-pyrazole-5-carboxamide.

Example 126

-   N-((5-chloro-1H-benzo[d]imidazol-4-yl)methyl)-N-(cyclobutylmethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 127

-   N-(2-chlorobenzyl)-N-(cyclobutylmethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 128

-   N-((3-chloropyridin-4-yl)methyl)-N-(cyclobutylmethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 129

-   N-(2-fluoro-4-hydroxybenzyl)-3-cyclopropyl-N-(3,3,3-trifluoropropyl)-1H-pyrazole-5-carboxamide.

Example 130

-   N-(2-fluoro-4-hydroxybenzyl)-3-(trifluoromethyl)-N-(3,3,3-trifluoropropyl)-1H-pyrazole-5-carboxamide.

Example 131

-   N-(2-fluoro-4-hydroxybenzyl)-3-(trifluoromethyl)-N-(3-hydroxy-3-methylbutyl)-1H-pyrazole-5-carboxamide.

Example 132

-   N-(2-fluoro-4-hydroxybenzyl)-N-cyclopentyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 133

-   N-(2-fluoro-4-hydroxybenzyl)-N-(2-aminoethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 134

-   N-(4-amino-2-chlorobenzyl)-N-(cyclobutylmethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 136

-   N-(3-fluoro-2-hydroxybenzyl)-N-(cyclobutylmethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 137

-   N-(2-fluoro-4-hydroxybenzyl)-3-(trifluoromethyl)-N-(2-hydroxyethyl)-1H-pyrazole-5-carboxamide.

Example 138

-   N-(2-fluoro-4-hydroxybenzyl)-3-(trifluoromethyl)-N-(2-hydroxy-2-methylpropyl)-1H-pyrazole-5-carboxamide.

Example 139

-   N-(2-fluoro-4-hydroxybenzyl)-N-cyclohexyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 140

-   N-(2-fluoro-4-hydroxybenzyl)-N-(2-cyclopropylethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 141

-   N-(3-chloro-2-hydroxybenzyl)-N-(cyclobutylmethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 142

-   N-(2-fluoro-4-hydroxybenzyl)-3-(trifluoromethyl)-N-(2-methoxyethyl)-1H-pyrazole-5-carboxamide.

Example 143

-   N-(2-fluoro-4-hydroxybenzyl)-N-(2-(diethylamino)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 144

-   N-((1H-benzo[d]imidazol-4-yl)methyl)-N-((1H-pyrazol-4-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 145

-   N-(2-(aminomethyl)benzyl)-N-(cyclobutylmethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 146

-   N-(2-fluoro-4-hydroxybenzyl)-3-(trifluoromethyl)-N-((isoxazol-4-yl)methyl)-1H-pyrazole-5-carboxamide.

Example 147

-   N-(cyclobutylmethyl)-3-(trifluoromethyl)-N-((5-(hydroxymethyl)furan-2-yl)methyl)-1H-pyrazole-5-carboxamide.

Example 148

-   N-(2-fluorobenzyl)-N-(2-(diethylamino)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 149

-   N-(2-fluorobenzyl)-N-(2-cyclopropylethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 150

-   N-(2-fluorobenzyl)-3-(trifluoromethyl)-N-((tetrahydrofuran-3-yl)methyl)-1H-pyrazole-5-carboxamide.

Example 151

-   N-(2-fluorobenzyl)-3-(trifluoromethyl)-N-(tetrahydrofuran-3-yl)-1H-pyrazole-5-carboxamide.

Example 152

-   N-(2-fluorobenzyl)-N-(1-ethylpyrrolidin-3-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 153

-   N-(2-fluorobenzyl)-N-cyclohexyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 154

-   N-(3-aminobenzyl)-N-(2-(diethylamino)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 155

-   N-(2-fluorobenzyl)-N-(2-(ethylamino)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 156

-   N-(2-(dipropylamino)ethyl)-N-(2-fluorobenzyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 157

-   N-(2-(diisopropylamino)ethyl)-N-(2-fluorobenzyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 158

-   N-(2-fluorobenzyl)-3-(trifluoromethyl)-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 159

-   N-(2-chlorobenzyl)-N-(2-(diethylamino)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 160

-   N-((1H-benzo[d]imidazol-4-yl)methyl)-N-(2-(diethylamino)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 161

-   N-((1H-indol-4-yl)methyl)-N-(2-(diethylamino)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 162

-   N-(2-chlorobenzyl)-3-(trifluoromethyl)-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 163

-   N-((1H-benzo[d]imidazol-7-yl)methyl)-3-(trifluoromethyl)-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 164

-   N-((1H-indol-4-yl)methyl)-3-(trifluoromethyl)-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 165

-   N-(2,4-dichlorobenzyl)-3-(trifluoromethyl)-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 166

-   N-(2,4-dichlorobenzyl)-N-(2-(diethylamino)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 167

-   N-(2,3-dichlorobenzyl)-N-(2-(diethylamino)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 168

-   N-(2,5-dichlorobenzyl)-N-(2-(diethylamino)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 169

-   N-(2,6-dichlorobenzyl)-N-(2-(diethylamino)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 170

-   N-(2-chloro-4-fluorobenzyl)-N-(2-(diethylamino)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

Example 171

-   N-(2-chloro-5-fluorobenzyl)-N-(2-(diethylamino)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 172

-   N-(2-chloro-6-fluorobenzyl)-N-(2-(diethylamino)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 173

-   N-(2-chlorobenzyl)-3-(trifluoromethyl)-N-(2-(piperidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 174

-   N-(2-chlorobenzyl)-3-(trifluoromethyl)-N-(2-morpholinoethyl)-1H-pyrazole-5-carboxamide.

Example 175

-   N-(2-chlorobenzyl)-3-bromo-N-(2-(diethylamino)ethyl)-1H-pyrazole-5-carboxamide.

Example 176

-   N-(2-chlorobenzyl)-3-chloro-N-(2-(diethylamino)ethyl)-1H-pyrazole-5-carboxamide.

Example 177

-   N-(2-chloro-6-fluorobenzyl)-3-(trifluoromethyl)-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 178

-   N-(2,6-dichlorobenzyl)-3-(trifluoromethyl)-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 179

-   N-(2-chloro-6-fluorobenzyl)-3-(trifluoromethyl)-N-(2-(piperidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 180

-   N-(2,6-dichlorobenzyl)-3-(trifluoromethyl)-N-(2-(piperidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 181

-   N-(2-chlorobenzyl)-3-(trifluoromethyl)-N-(2-(pyrrolidin-1-yl)propyl)-1H-pyrazole-5-carboxamide.

Example 182

-   N-(2-chloro-3-fluorobenzyl)-N-(2-(diethylamino)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 183

-   N-(5-amino-2-chlorobenzyl)-N-(2-(diethylamino)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 184

-   N-(2-isopropylbenzyl)-N-(2-(diethylamino)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 185

-   N-(2-chlorobenzyl)-N-(3-(diethylamino)propyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 186

-   N-(2-chlorobenzyl)-N-(3-(dimethylamino)propyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 187

-   N-(2-chlorobenzyl)-N-(2-(dimethylamino)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 188

-   N-(2-chlorobenzyl)-3-(trifluoromethyl)-N-(2-(3,5-dimethylpiperidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 189

-   N-(2-chlorobenzyl)-N-(2-(azepan-1-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 190

-   N-(2-chlorobenzyl)-3-(trifluoromethyl)-N-(2-(4-methylpiperidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide

Example 191

-   N-(2-chlorobenzyl)-3-(trifluoromethyl)-N-(2-(3-methylpiperidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 192

-   N-(2-chlorobenzyl)-3-(trifluoromethyl)-N-(2-(2-methylpiperidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 193

-   N-(2-chlorobenzyl)-3-chloro-N-(2-(diethylamino)ethyl)-4-fluoro-1H-pyrazole-5-carboxamide.

Example 194

-   N-(2-chloro-4-hydroxybenzyl)-N-(2-(azepan-1-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 195

-   N-(2-fluoro-4-hydroxybenzyl)-N-(2-(azepan-1-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 196

-   N-(5-amino-2-chlorobenzyl)-N-(2-(azepan-1-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 197

-   N-(2-fluorobenzyl)-N-(2-(azepan-1-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 198

-   N-(2,6-difluorobenzyl)-N-(2-(azepan-1-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 199

-   N-(2-chlorobenzyl)-N-(2-(4-ethylpiperidin-1-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 200

-   N-(5-amino-2-chlorobenzyl)-3-(trifluoromethyl)-N-(2-(3-methylpiperidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 201

-   N-(2-fluorobenzyl)-3-(trifluoromethyl)-N-(2-(3-methylpiperidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 202

-   N-(5-amino-2-chlorobenzyl)-3-(trifluoromethyl)-N-(2-(2-methylpiperidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 203

-   N-(2-fluorobenzyl)-3-(trifluoromethyl)-N-(2-(2-methylpiperidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 204

-   N-(2-chlorobenzyl)-N-(2-(ethyl-isopropylamino)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 205

-   N-(2-chlorobenzyl)-3-(trifluoromethyl)-N-(2-(4,4-difluoropiperidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 206

-   N-((3-fluoro-1H-indol-4-yl)methyl)-3-(trifluoromethyl)-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 207

-   N-(4-amino-2-chlorobenzyl)-N-(2-(azepan-1-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 208

-   N-((1H-benzo[d]imidazol-7-yl)methyl)-N-(2-(azepan-1-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 209

-   N-(2-chlorobenzyl)-N-(2-(ethyl-propylamino)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 210

-   N-(2-chloro-3-nitrobenzyl)-N-(2-(azepan-1-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 211

-   N-(2-chloro-6-nitrobenzyl)-N-(2-(azepan-1-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 212

-   N-(2-chlorobenzyl)-3-(trifluoromethyl)-N-(2-(2,6-dimethylpiperidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 213

-   N-(3-amino-2-chlorobenzyl)-N-(2-(azepan-1-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 214

-   N-(5-amino-2-fluorobenzyl)-N-(2-(azepan-1-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 215

-   N-(5-amino-2-methoxybenzyl)-N-(2-(azepan-1-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 216

-   N-(3-amino-2-fluorobenzyl)-N-(2-(azepan-1-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 217

-   N-(3-amino-2-methoxybenzyl)-N-(2-(azepan-1-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 218

-   N-(2-amino-6-chlorobenzyl)-N-(2-(azepan-1-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 219

-   N-(2-chlorobenzyl)-3-(trifluoromethyl)-N-(2-(4-hydroxypiperidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 220

-   N-(2-chlorobenzyl)-3-(trifluoromethyl)-N-(2-(3-hydroxypiperidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 221

-   N-(2-amino-6-chlorobenzyl)-3-(trifluoromethyl)-N-(2-(pyrrolidin-1-yl)propyl)-1H-pyrazole-5-carboxamide.

Example 222

-   N-(2-amino-6-chlorobenzyl)-3-(trifluoromethyl)-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 223

-   N-(2-chloro-6-aminobenzyl)-N-(2-(ethyl-propylamino)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 224

-   N-(2-amino-6-chlorobenzyl)-N-(2-(4-dioxothiomorpholino)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 225

-   N-(2-amino-6-chlorobenzyl)-3-(trifluoromethyl)-N-(2-(3-hydroxypiperidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 226

-   N-(2-chlorobenzyl)-N-(3-aminocyclobutyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 227

-   N-(2-chlorobenzyl)-N-((azetidin-2-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 228

-   N-(2-chlorobenzyl)-N-(2-(1-(methylsulfonyl)piperidin-3-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 229

-   N-(2-chlorobenzyl)-3-(trifluoromethyl)-N-phenethyl-1H-pyrazole-5-carboxamide.

Example 230

-   N-(2-chlorobenzyl)-N-(4-hydroxyphenethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 231

-   N-(2-chlorobenzyl)-N-((1-ethylpyrrolidin-2-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 232

-   N-(2-chlorobenzyl)-3-(trifluoromethyl)-N-((pyrrolidin-2-yl)methyl)-1H-pyrazole-5-carboxamide.

Example 233

-   N-(2-amino-6-chlorobenzyl)-N-((azetidin-2-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 234

-   N-(2-amino-6-chlorobenzyl)-3-(trifluoromethyl)-N-(2-(3-hydroxypyrrolidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 235

-   N-(2-amino-6-chlorobenzyl)-3-(trifluoromethyl)-N-(2-(3-methoxypyrrolidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 236

-   N-(2-amino-6-chlorobenzyl)-3-(trifluoromethyl)-N-(2-(3-fluoropiperidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 237

-   N-(2-amino-6-chlorobenzyl)-3-(trifluoromethyl)-N-(2-(3-methoxypiperidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 238

-   N-(2-amino-6-chlorobenzyl)-3-(trifluoromethyl)-N-(2-(4-fluoropiperidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 239

-   N-(2-(1,4-oxazepan-4-yl)ethyl)-N-(2-amino-6-chlorobenzyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide’

Example 240

-   N-(2-fluoro-6-aminobenzyl)-N-(2-(ethyl-propylamino)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 241

-   N-(2-amino-6-chlorobenzyl)-3-(trifluoromethyl)-N-(2-((S)-3-fluoropyrrolidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 242

-   N-(2-amino-6-chlorobenzyl)-3-(trifluoromethyl)-N-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide.

Example 243

-   N-(2-amino-6-chlorobenzyl)-N-(2-(4-fluoroazepan-1-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

Example 244

-   N-(2-fluoro-4-hydroxybenzyl)-3-chloro-N-(cyclobutylmethyl)-1H-pyrazole-5-carboxamide.

Example 1173-chloro-N-(cyclobutylmethyl)-N-((3-fluoropyridine-N-oxide-4-yl)methyl)-1H-pyrazole-5-carboxamide

3-Chloro-N-(cyclobutylmethyl)-N-((3-fluoropyridin-4-yl)methyl)-1H-pyrazole-5-carboxamide(46 mg, 0.143 mmol) was dissolved in DCM (1.5 mL) and cooled to 0 C. Ina separate vial, MCPBA (30 mg, 0.135 mmol) was dissolved in DCM (1 mL)and cooled to 0 C. The MCPBA solution was added dropwise to the solutioncontaining reactant 1 and the resulting solution was stirred for 1 h.The reaction mixture was then washed with 3 portions of 1 N NaOH (2 mL)and the solvent removed in vacuo. The product was then purified vianormal phase chromatography (DCM/MeOH, 0→10%). The purity of the desiredproduct was still too low so the product was re-purified via semi-prepHPLC (ACN/Water+0.05% TFA) to give the product in greater than 99%purity.

Example 1183-chloro-N-(cyclobutylmethyl)-N-((3-((dimethylamino)methyl)-1H-indol-4-yl)methyl)-1H-pyrazole-5-carboxamide

To a solution of dimethyl amine (109 uL of 2 molar, 0.218 mmol) in AcOH(1 mL) was added formaldehyde (7.91 uL of 38% aqueous, 0.109 mmol).After stirring for 15 min a solution ofN-((1H-indol-4-yl)methyl)-3-chloro-N-(cyclobutylmethyl)-1H-pyrazole-5-carboxamide(34 mg, 0.099 mmol) in acetic acid (1 mL) was added. The reaction wasstirred overnight at 75° C. then cooled to room temperature and dilutedwith EtOAc (3 mL) and washed with saturated potassium carbonate solution(3 mL) twice and water (2 mL) once. The organic layer was then strippedin vacuo and the product purified by normal phase chromatography(DCM/MeOH, 0→20%). After isolation of the product the purity was nothigh enough so it was repurified by semi prep HPLC (ACN/Water+0.05% TFA)to give the desired product in 97% purity.

Example 135N-((1H-indol-4-yl)methyl)-N′-cyclobutyl-3-(trifluoromethyl)-1H-pyrazole-5-carbohydrazide

A mixture of 1H-indole-4-carbaldehyde (296 mg, 2.039 mmol),cyclobutylhydrazine, HCl (250 mg, 2.039 mmol), sodium carbonate andMgSO4 (491 mg, 4.08 mmol) in methanol was stirred overnight. The solidswere then removed by filtrated and the resulting solution diluted withIPA. The resulting hydrazone was then reduced by hydrogenation using anH-Cube continuous flow hydrogenator (75 bar 55 C with Pd/C catalystcartridge, 0.8 mL/min). After reduction the resulting hydrazine wascoupled with the trifluoromethylpyrazole in the standard fashion to giveExample 135 as a minor product that was isolated by reverse phasechromatography.

Example 193N-(2-chlorobenzyl)-3-chloro-N-(2-(diethylamino)ethyl)-4-fluoro-1H-pyrazole-5-carboxamide

Preparation of 3-chloro-4-fluoro-1H-pyrazole-5-carboxylic acid for thesynthesis of Example 193 via amide coupling is shown below.

3-chloro-1H-pyrazole-5-carboxylic acid (200 mg, 1.37 mmol) was suspendedin acetonitrile (3 mL) followed by the addition Selectfluor 11(550 mg,1.55 mmol) and acetic acid (500 g, 8.33 mmol). The mixture was submittedto microwave irradiation, maintaining the temperature at 100 C for 2 h.An additional 550 mg of Selectfluor II was added and the reactionreturned to the microwave where the temperature was maintained at 100 Cfor 1 h. The reaction mixture was diluted with 3 mL of EtOAc then washedwith water (5 mL) three times. The solvent was stripped in vacuo and3-chloro-4-fluoro-1H-pyrazole-5-carboxylic acid was isolated by semiprep HPLC (ACN/water+0.05% TFA).

Example 206

1H-indole-4-carbaldehyde (2.26 g, 15.5 mmol) was added to Acetonitrile(20 mL) followed by acetic acid (2.25 mL, 39 mmol). The reaction mixturewas cooled to 0 C and Selectfluor (2.5 g, 17.1 mmol) was addedportion-wise over the course of 15 min. The reaction was aged for 3hours then diluted with 15 mL of EtOAc and washed with water (25 mL) 3times. The organics were then stripped in vacuo and the crude productpurified via normal phase MPLC (100% DCM).

Example 238

4-Fluoropiperidine HCl (801 mg, 5.74 mmol) was added dropwise to astirred aqueous solution of glycolonitrile (647 uL of a 52% aqueoussolution, 6.31 mmol) at 5° C. Sodium carbonate (912 mg, 8.60 mmol) wasadded and the solution was stirred at 70° C. for 1.5 h. The solution wascooled, diluted with water (2 mL), washed with Et2O (3×4 ml). Theorganic fraction was dried and the solvent evaporated to give2-(4-fluoropiperidin-1-yl)acetonitrile as a colourless oil. The oil wasthen dissolved in a 7 N solution of ammonia in MeOH (25 mL) andsubmitted to hydrogenation on the H-Cube using 75 bar of hydrogenpressure at 55 C with a flow rate of 0.8 mL/min and using a Raney nickelcatalyst cartridge. After the reaction was complete the solvent wasstripped in vacuo to give 2-(4-fluoropiperidin-1-yl)ethanamine as atranslucent oil.

Examples 219, 220, 225, 234, 235, 236, 237, 238, 239, 241, 242, 243

The aminoethyl side chain was prepared using a method analogous to theprocedure exemplified in example 238. The remaining portions of thecompound were prepared using methods analogous to those described above.

Examples 213-218, 221-225, 233-239, 241-243

The nitro group was reduced as demonstrated in example 96

Examples 133, 155, 226, 227, 232

The boc-protected analogue was used in each example. The deprotectionwas carried out as described in example 11

Examples 183, 196, 200, 202, 240

The Boc-protected analogue was used in each example. The deprotectionwas carried out as described in example 91

Example 245 Crystallography and Assays

Full length, human PKM2 enzyme was obtained from Promab (Richmond,Calif.). All reagents, unless otherwise noted, were obtained from Sigma(St. Louis, Mo.). Cell lines were obtained from ATCC (Manassas, Va.).Media was obtained from Invitrogen (Grand Island, N.Y.).

PKM2 Biochemical Assay

Compounds were pre-incubated with 2 nM PKM2 in reaction buffer (50 mMTris-HCl, pH 8.0, 200 mM KCl, 30 mM MgCl₂, 2 mM DTT, 5% DMSO) for 30 minat ambient temperature. ADP and PEP were then added to finalconcentrations of 75 μM and 15 μM, respectively. After 30 min, ATPformation was measured by Kinase Glo (Promega, Madison, Wis.), and AC₅₀values were determined using Prism (GraphPad Software, Inc., La Jolla,Calif.).

FIG. 1B shows representative PKM2 activity dose-response curves for FBP,Example 244 and Example 1. Maximal PKM2 activity for all three compoundswas approximately 600% relative to activity in DMSO controls (normalizedto 100%±SD).

FIG. 1C depicts normalized PKM2 activity dose-response curves (±SD) forPEP in the presence of 1 mM ADP plus 1 μM FBP, Example 244, Example 1,or DMSO control. EC₅₀ values calculated for PEP: FBP (15 μM); Example244 (15 μM), Example 1 (18 μM); DMSO (87 μM).

FIG. 1D illustrates normalized PKM2 activity dose response curves (±SD)for ADP in the presence 1 mM PEP plus 1 μM FBP, Example 244, Example),or DMSO control. EC₅₀ values for PEP: FBP (62 μM); Example 244 (47 μM),Example 1 (45 μM); DMSO (61 μM)

Potency data for representative compounds is shown in Table 2.

TABLE 2 PKM2 biochemical activation profiles for FBP and representativecompounds. FBP Example 244 Example 1 ^(†)AC₅₀ 23 ± 8 nM 62 ± 23 nM 11 ±4 nM (n = 10) (n = 6) (n = 6) ^(††)% FBP 100 ± 0    107 ± 10    104 ±11    (n = 10) (n = 6) (n = 6) Molecular 340 338 382 Weight clogP   −3.0   3.3    3.1 ^(†)AC₅₀ indicates the concentration of half-maximal PKM2activation. ^(††)% FBP indicates the extent of maximal activation,relative to FBP (normalized to 100%).

X-Ray Crystallography

A publically available human PKM2 (hPKM2) expression construct wasobtained from the Structural Genomics Consortium (SGC). His6-hPKM2 waspurified using NiNTA affinity capture and Hiload Superdex 16/60 S75 sizeexclusion chromatography. hPKM2 was crystallized using hanging dropvapor diffusion. Protein solution (20 mg/ml, 25 mM Tris/HCl pH 7.5, 0.1M KCL, 5 mM MgCl2, 10% (v/v) glycerol) was mixed in a 1:1 ratio withreservoir solution containing 0.1 M KCl, 0.1 M ammonium tartrate, 25%(w/v) PEG3350. Crystals were soaked overnight in a solution containing 2mM Example 244, cryo-protected and flash frozen in liquid N2. X-raydiffraction data were collected from a single crystal at 100K atBeamline-ID29 at the ESRF. Diffraction data were processed using XDSAutoPROC from Global Phasing and SCALA (CCP4) (32). Molecularreplacement was performed using model 3H6O (SGC) in CSEARCH (33) andmaximum likelihood refinement carried out using a mixture of automated(34) and manual refinement protocols employing Refmac (CCP4). Ligandfitting was performed using Autosolve (33) and manual rebuilding. Eachof the four PKM2 monomers and four activator ligands, comprising thetetramer in the asymmetric unit, were refined as independent entities.

Cell-Based Pyruvate Kinase Activity Assay

A549 or NCI-H1299 lung cancer cells were plated at 20,000 cells per well(96-well plate) in MEM media plus 10% FBS, with no additional glutamineor pyruvate. Following overnight incubation, cells were washed with PBSfollowed by 4 hour incubation in MEM media. Compounds were added to thecells in 1% final concentration DMSO. After 30 minutes, cells werelysed, and pyruvate kinase activity in lysates was determined byPyruvate Kinase Activity Assay (BioVision, Milpitas, Calif.). Maximumvelocity values were calculated from the kinetic data, and AC50 valueswere determined using Prism GraphPad Software (La Jolla, Calif.).Compound washout experiments were as described above, except after a 30minute incubation with Example 244 (469 nM), the cells were washed withPBS followed by the addition of MEM media for the indicated time period,lysed and pyruvate kinase activity determined. Results are tabulated inTable 3 and presented graphically in FIGS. 6A and 6B.

TABLE 3 Cellular PKM2 activation profiles for Representative Compounds.Example 244 Example 1 Cell line EC₅₀ (nM) EC₅₀ (nM) A549 450 ± 180 260 ±120 (n = 4) (n = 4) NCI-H1299 300 ± 70  220 ± 50  (n = 4) (n = 4)

Cell-Based Tetramer Formation Assay

HEK-293 cells were stably transfected with FLAG-PKM2 (Origene,Rockville, Md.) and grown in RPMI 1640 media. When the cells were 80%confluent in a 6-well plate, the cells were washed with PBS followed bya 3 hour incubation in minimal essential medium (MEM) without pyruvate.Compounds were added in 1% final concentration DMSO. Following 3 hoursof incubation with compounds, the cells were washed, lysed in 1% TritonX-100 buffer and immunoprecipitated with FLAG-M2-agarose beads (Sigma,St. Louis, Mo.). Eluted proteins from the immunoprecipitation wereseparated by SDS gel electrophoresis followed by Western blotting usinganti-FLAG M2 antibody (Sigma, St. Louis, Mo.). The increased endogenousPKM2 that co-immunoprecipitated with FLAG-PKM2 indicates tetramerformation. See FIGS. 3B and 7.

Cell Proliferation Assay

Cells were seeded at 5000 cells per well (in 96-well plate) in BME medialacking nonessential amino acids+5% dialyzed serum. After 18 hours, DMSOor compound in 0.1% final concentration DMSO was added. After 72 hours,cell viability was determined by ATPlite assay and EC50 values weredetermined using Prism GraphPad Software (La Jolla, Calif.) (FIG. 4A).

Serine rescue experiments were performed as above with the exceptionthat 30 μM serine was added simultaneously with compound. Statisticalanalysis was performed by parametric ANOVA test. *p<0.002 (Example 244or Example 244+serine vs. DMSO). **p<0.0005 (Example 1 or Example1+serine vs. DMSO) (FIG. 4B).

Viability effect of Example 1 against a subset of lung carcinoma celllines was determined as follows. Cells were seeded at 1500 cells perwell in 384-well plates in BME media, and compound was added in 0.1%DMSO 18 hours later. Viability was determined by ATPlite assay after 72hours. (See FIG. 4C).

Example 1 was tested against an expanded panel of cell lines accordingto the above procedure. Results (IC₅₀) are presented in Table 4.

TABLE 4 Cell Line Sensitivity to Example 1 Sensitivity to Sensitivity toIndication Cell line Serine Example 1 Bladder UMUC-3 Sensitive >30 μMBrain A172 Insensitive 2.3 μM Breast MDA-MB453 Sensitive >30 μMMDA-MB468 Insensitive >30 μM MCF7 Sensitive >30 μM Colon HCT15Insensitive >30 μM HCT116 Sensitive 100 nM HT29 Sensitive 100 nM Ls174TInsensitive >30 μM RKO Sensitive >30 μM SW48 Sensitive >30 μM SW480Insensitive 100 nM SW620 Sensitive 200 nM SW948 Insensitive >30 μM GISTGist882 Insensitive 800 nM Head/Neck Detroit562 Sensitive 3 μM FaDuSensitive >30 μM Kidney 786-O Sensitive >30 μM A498 Insensitive >30 μMCaki-1 Insensitive 80 nM ACHN Insensitive 100 nM Liver HepG2Insensitive >30 μM Lung A549 Sensitive 100 nM H1299 Insensitive 600 nMNCl-H460 Sensitive 5 μM NCl-H647 Sensitive >30 μM NCl-H23 InsensitiveN/A NCl-H522 Insensitive >30 μM NCl-H1975 Sensitive 90 nM NCl-H441Sensitive N/A Melanoma Malme3M Insensitive >30 μM Ovarian OVCAR-3Sensitive 20 nM Skov3 Sensitive 8 μM Pancreatic AsPC1 Sensitive >30 μMCapan1 Insensitive >30 μM Capan2 Sensitive >30 μM Panc-1 Insensitive 14nM Hs766T Insensitive 300 nM PSN-1 Sensitive >30 μM MiaPaCa2 Sensitive200 nM PL45 Sensitive >30 μM Prostate 22RV1 Insensitive >30 μM Du145Insensitive >30 μM LNCaP Sensitive >30 μM PC3 Sensitive 100 nM SarcomaHT1080 Sensitive 50 nM

Percent viability (EC₅₀) of A549 and PC3 cells was tested againstcertain exemplary compounds according to the above general procedures.Results are presented in Table 5 and FIG. 8.

TABLE 5 Viability of A549 and PC3 Cells in the Presence of ExemplaryCompounds A549 PC3 Average (nM) STD Average (nM) STD Ex. 236 8.1 0.733.0 4.7 Ex. 91 20.3 0.7 47.3 22.0 Ex. 223 33.5 4.4 54.0 1.0 Ex. 23445.8 17.3 92.4 26.8 Ex. 1 70.0 2.6 155.5 17.5 Ex. 239 73.1 4.3 128.7 6.4Ex. 54 101.7 34.3 192.7 44.1 Ex. 62 107.6 15.3 166.1 24.5 Ex. 75 147.97.8 222.9 23.2 Ex. 47 188.4 56.1 383.0 130.4 Ex. 227 928.5 353.1 1311.574.2

Xenograft Experiments

Female athymic Nu/Nu mice were implanted with 10⁷ A549-luc-C8 cells in1:1 volume with Matrigel into the right hind flank on day 1, followed bybioluminescent measurement and randomization for each group (n=15 forxenograft study in FIG. 5A; n=18 for xenograft study in FIG. 5B). Micewere dosed intraperitoneally starting on day 1 with either vehicle (5%Ethanol/7.5% DMSO/25% PEG400/12.5% Cremophor EL/50% D5 water) or vehicleplus compound at a dose of 50 mg/kg, once daily, 5 days on, 2 days off,for 5 weeks. Tumor volumes were determined by caliper measurementstarting on day 7 after implantation. Statistical significance at day 31was determined by Student's t-test. Body weight data for the aboveexperiment is presented in FIG. 9.

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon-patent publications referred to in this specification areincorporated herein by reference in their entirety including U.S.Provisional Appliction No. 61/714,659 filed Oct. 16, 2012 and U.S.Provisional Patent Application No. 61/875,844 filed Sep. 10, 2013, tothe extent not inconsistent with the present description.

From the foregoing it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention. Accordingly, the invention is notlimited except as by the appended claims.

1. A compound having the following structure (I):

or a stereoisomer, pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein: R¹ is cycloalkyl or haloalkyl; R² is H; R³ is alkyl or heterocyclyalkyl; R⁴ aryl; R⁵ and R⁶ are each H. 2-3. (canceled)
 4. The compound of claim 1, wherein R⁴ has the following structure (A);

wherein: R⁷ and R⁸ are each independently H, alkyl, alkoxy, halo, hydroxyl, hydroxylalkyl, amino, aminoalkyl, alkylaminoalkyl, nitrile, nitro, —O(CH₂)_(m)P(═O)(OH)₂ or amino acid ester.
 5. (canceled)
 6. The compound of claim 3, wherein R⁷ and R⁸ are each independently H, halo or amino.
 7. The compound of claim 4, wherein R⁴ has the following structure:


8. The compound of claim 7, wherein R⁷ is H or amino.
 9. The compound of claim wherein R⁸ is chloro or fluoro.
 10. The compound of claim 1, wherein R⁴ has one of the following structures:

11-20. (canceled)
 21. The compound of claim 1, wherein R³ has one of the following structures (D), (E) or (F):

wherein: Q is CH₂, O, NR¹³, CF₂, or S(O)_(w); B is O, NR¹⁴ or

R⁹, R¹¹ and R¹³ are each independently H or alkyl; R¹⁰ is H, H hydroxyl, halo, alkoxy or alkyl; R¹² is H, amino or alkoxy; R¹⁴ is H, alkyl or alkyl sulfone; q are each independently 0, 1 or 2; r, s and v are each independently 1 or 2; t is 1, 2 or 3; and u is 0, 1, 2 or
 3. 22. The compound of claim 21, wherein R³ has structure (D).
 23. The compound of claim 22, wherein s is
 1. 24. The compound of claim 22, wherein s is
 2. 25. The compound of claim 23, wherein r is
 1. 26. The compound of claim 23, wherein r is
 2. 27. The compound of claim 23, wherein q is
 0. 28. The compound of claim 23, wherein q is
 1. 29. The compound of claim 23, wherein q is
 2. 30. The compound of claim 1, wherein R³ has one of the following structures:


31. The compound of claim 21, wherein R³ has structure (E).
 32. The compound of claim 31, wherein Q is CH₂.
 33. The compound of claim 31, wherein Q is SO₂.
 34. The compound of claim 31, wherein Q is O.
 35. The compound of claim 31, wherein Q is CHF₂.
 36. The compound of claim 31, wherein Q is NR¹³.
 37. The compound of claim 35, wherein R¹³ is methyl or ethyl.
 38. The compound of claim 31, wherein R¹⁰ and R¹¹ are each H.
 39. The compound of claim 31, wherein R¹⁰ is methyl, fluoro, hydroxyl or methoxy.
 40. The compound of claim 1, wherein R³ has one of the following structures:


41. The compound of claim 21, wherein R³ has structure (F).
 42. (canceled)
 43. The compound of claim 41, wherein R¹² is H.
 44. The compound of claim 41, wherein R¹² is alkoxy.
 45. The compound of claim 41, wherein R¹² is methoxy, ethoxy or isopropoxy.
 46. The compound of claim 1, wherein R³ has one of the following structures:


47. (canceled)
 48. The compound of claim 1, wherein R³ is alkyl.
 49. The compound of claim 8, wherein the alkyl is substituted with one or more substituents selected from hydroxyl, halo, amino, alkylamino, alkoxy and alkylsulfone. 50-55. (canceled)
 56. The compound of claim 1, wherein R¹ is CF₃. 57-58. (canceled)
 59. The compound of claim 1, wherein R¹ is cyclopropyl. 60-61. (canceled)
 62. The compound of claim 1, wherein the compound has the following structure (Ia):

or a stereoisomer, pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein: R¹⁵ is halo; R¹⁶ is H or NH₂; and w is 1 or
 2. 63. The compound of claim 62, wherein R¹⁵ is chloro.
 64. The compound of claim 62, wherein R¹⁵ is fluoro.
 65. The compound of claim 62, wherein R¹⁶ is H.
 66. The compound of claim 62, wherein R¹⁶ is NH₂.
 67. The compound of claim 62, wherein w is
 1. 68. The compound of claim 62, wherein w is
 2. 69. The compound of claim 1, wherein the compound has the following structure (Ib):

or a stereoisomer, pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein: R¹⁷ is halo; R¹⁸ is H or NH₂; Z is CH₂, O, NH, NR¹⁹, CHR²⁰ or CF₂; R¹⁹ is alkyl; R²⁰ is alkoxy, hydroxyl or halo; and x is 0, 1, 2 or
 3. 70. The compound of claim 69, wherein R¹⁷ is chloro.
 71. The compound of claim 69, wherein R¹⁸ is NH₂.
 72. The compound of claim 69, wherein Z is CHOH.
 73. The compound of claim 69, wherein Z is CHOCH₃.
 74. The compound of claim 69, wherein Z is CHF.
 75. The compound of claim 69, wherein Z is O.
 76. The compound of claim 69, wherein x is
 1. 77. The compound of claim 69, wherein x is
 2. 78-84. (canceled)
 85. The compound of claim 1, wherein the compound has one of the following structures:

86-90. (canceled) 